JP2017513828A - Amide derivatives and their pharmaceutically acceptable salts, methods for their preparation and their pharmaceutical applications - Google Patents

Abstract

The present invention relates to amide derivatives and their pharmaceutically acceptable salts, processes for their preparation and their pharmaceutical applications. Specifically, the present invention relates to amide derivatives represented by the general formula (I), methods for producing them, pharmaceutical compositions containing the derivatives, and therapeutic agents, in particular, microsomal prostaglandin E synthase-1 ( It relates to their use as inhibitors of mPGES-1) and their use in the manufacture of a medicament for the treatment and / or prevention of diseases or conditions such as inflammation and / or pain. The definition of each substituent in general formula (I) is the same as the definition in the specification. [Selection figure] None

Description

  The present invention relates to novel amide derivatives, methods for their preparation and pharmaceutical compositions containing them, and use as therapeutic agents, in particular as inhibitors of microsomal prostaglandin E synthase-1 (mPGES-1), and It relates to their use in the manufacture of a medicament for the treatment and / or prevention of diseases or disorders such as inflammation and / or pain.

  Many diseases or disorders are inflammatory in nature. A major existing problem with the treatment of inflammatory diseases is the lack of efficacy and / or the presence of common side effects. Inflammatory diseases relating to humans include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis, dermatitis and the like. Inflammation is a common cause of pain and can be caused by various reasons such as infection, surgery, or other injuries. On the other hand, some diseases such as malignant tumors and cardiovascular diseases also have symptoms of inflammation.

  Prostaglandin E2 (Prostaglandin E2, PGE2) is one of the most common prostaglandins (PGs), belonging to a strong pro-inflammatory mediator, inducing fever and pain, Involved in physiological and pathological processes. Its chemical synthesis consists of three consecutive enzymatic reactions: (1) arachidonic acid (AA) is released from glycerin phospholipids on the membrane by the catalytic action of phospholipase A2 (PLA2); , AA produces PGG2 and PGH2; (3) PGH2 produces PGE2, PGF2, PGD2, prostacyclin and thromboxane A2 by the catalytic action of PGE2 synthase (PGES).

  There are two forms of cyclooxygenase (COX). One is constitutively expressed as COX-1 in many cells and tissues, and the other is COX-2 that is induced by proinflammatory stimuli such as cytokines during the inflammatory reaction. Various COX-1 to control inflammation by reducing the final production of PGE2, such as “NSAID” (non-steroidal anti-inflammatory drug) and “coxib” (COX-2 selective inhibitor) And / or a COX-2 inhibitor. However, inhibiting target COX reduces the production of all metabolites from arachidonic acid (AA), including some metabolites that are beneficial to the human body. COX inhibitors can therefore cause harmful biological effects on the human body. Thus, developing new drugs for safer and more effective inflammatory diseases has great clinical significance and market value.

  Prostaglandin E synthase (PGES), which targets prostaglandin E2 (PGE2) synthesis, is the final rate-limiting enzyme in the process of PGE2 synthesis. As is well known, at least three types of PGES, called cytoplasmic PGES (cPGES) (or PGE-3), membrane-bound PGES-1 (mPGES-1) and membrane-bound PGES-2 (mPGES-2) There is. cPGES is a GSH-dependent resident enzyme and belongs to an enzyme that is widely expressed by housekeeping genes in many tissues and cells and is not affected by inflammatory stimulating factors. mPGES-2 is a GSH-independent resident enzyme, and is mainly expressed in tissues with relatively low expression of mPGES-1, such as brain, heart, kidney, and intestine, and is not induced by tissue inflammation or damage. mPGES-1 belongs to a GSH-dependent inducible expression enzyme, and is expressed in large quantities by being induced by inflammatory factors, causing arthritis, inflammation-related fever and pain, atherosclerosis, and cancer pathology and It plays an important role in various diseases such as physiological processes. The gene for mPGES-1 is on chromosome 9q34.3, contains 3 exons and 2 introns, and has a length of approximately 14.8 Kb. The cDNA encodes a polypeptide containing 152 amino acids. MPGES-1 primary protein structures from different species have over 80% homology. Studies have shown that COX-2 and mPGES-1 expression is markedly increased in various cultured cells upon stimulation with inflammatory factors (LPS, IL-1, etc.), which is accompanied by an increase in PGE2 synthesis. In immunohistochemistry experiments, COX-2 and mPGES-1 are all located in the microsomal membrane, which binds mainly to COX-2 and causes PGE2 synthesis in a delayed reaction caused by inflammatory factors. Indicates that it mediates an increase. However, enzyme kinetic studies have shown that the induction of COX-2 and mPGES-1 is not completely consistent; in some cases, COX-2 can bind to mPGES-2 and mPGES-1 also At the same time, it can bind to COX-1. Furthermore, PGH2 produced by the catalyst of COX-2 is synthesized into PGE2, or synthesized into other types of prostaglandins by the action of mPGES-1. Therefore, the regulatory mechanisms of COX-2 and mPGES-1 expression overlap and are different.

  Currently, there are two types of mPGES-1 inhibitors, Korea GNT (Neurotech) pharmaceutical company AAD-2004 and Eli Lilly's LY-3023703. The indications for AAD-2004 are not intended for pain, but are potent spin trapping molecules and microsomal prostaglandin E synthase-1 inhibitors that can be used to treat Alzheimer's disease, Parkinson's disease and motor neuron disease. LY-3023703 was used to treat osteoarthritis pain and entered the clinical phase in June 2016. Currently, there are only two patent applications, patent documents 1 and 2, for mPGES-1 disclosed by Eli Lilly.

WO2012087771 WO2012161965

  Although a series of microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have been disclosed so far, there is still a need to develop new compounds with better effects. In the present invention, a series of compounds of the general formula (I) was obtained by continuous efforts, and it was found that these compounds have excellent effects and functions.

The present invention relates to compounds of formula (I), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
In the formula:
Ring P is selected from 5-membered heteroaryl and 5-membered heterocyclyl;
Ring Q is selected from aryl and heteroaryl, preferably phenyl, pyridyl or pyrimidinyl;
A, B or Y is selected from -CH and N;
R ¹ is selected from alkyl and cycloalkyl, which alkyl or cycloalkyl may be optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen and haloalkyl;
R ² is selected from halogen and haloalkyl;
R ³ is the same or different and each independently represents hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, oxo, —C (O) OR ⁵ , —OC (O) R ⁵ , —NHS ( O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C (O) Selected from NR ⁶ R ⁷ , wherein the alkyl, cycloalkyl and heterocyclyl are each halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC Optionally further substituted with one or more groups selected from the group consisting of (O) NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ ;
R ⁴ is selected from aryl and heteroaryl, preferably phenyl, each aryl and heteroaryl being halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,- C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , —OC (O) NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ may be optionally further substituted with one or more groups selected from the group consisting of Fluoromethyl;
R ⁵ is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are each alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Optionally further substituted with one or more groups selected from the group consisting of aryl, heteroaryl, carboxylic acid and carboxylate groups;
R ⁶ and R ⁷ are each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each alkyl, halogen, Optionally substituted with one or more groups selected from the group consisting of hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate groups; or
R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a heterocyclyl, wherein the heterocyclyl is one or more selected from the group consisting of N, O and S (O) _m It may contain heteroatoms, and the heterocyclyl is one or more selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate groups Optionally substituted with a group;
m is 0, 1 or 2;
s is an integer from 0 to 3;
t is 0 or 1.

In a preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof And when R ² is halogen, t is 1.

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof The salt is a compound of formula (II), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
In the formula:
X is selected from -CH- and N;
Rings P, A, B, Y, s, t and R ^{1 to} R ⁴ are as defined in general formula (I).

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof The salt is a compound of formula (III), formula (IV), or formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or A pharmaceutically acceptable salt:
In the formula:
X is selected from -CH- and N;
E, G and W are each independently selected from CR ^a , NR ^b , N, O and S;
R ^a and R ^b are each independently hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C (O) NR ⁶ R ⁷ is selected from the alkyl, cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} - OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) Optionally further substituted with one or more groups selected from the group consisting of NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ ; and
A, B, Y, t, R ^{1 to} R ² and R ^{4 to} R ⁷ are as defined in the general formula (I).

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof The salt is a compound of formula (VI), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
In the formula:
X is selected from -CH- and N;
R ^b is hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} -OC (O) R 5, - NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C ( O) one or more groups selected from the group consisting of NR ⁶ R ⁷ ; preferably further optionally substituted with C _1-4 alkyl, C _1-4 alkoxy or tetrahydrofuryl;
A, B, Y, t, R ^{1 to} R ² and R ^{4 to} R ⁷ are as defined in the general formula (I).

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof The salt is a compound of formula (VII), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
In the formula:
X is selected from -CH- and N;
R ^b is hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} -OC (O) R 5, - NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C ( O) optionally further substituted with one or more groups selected from the group consisting of NR ⁶ R ⁷ ;
R ⁸ is halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C (O) OR ⁵ , —OC (O) R ⁵ , —NHS ( O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ or -C (O) Selected from NR ⁶ R ⁷ , wherein the haloalkyl is preferably trifluoromethyl; and
A, B, Y, R ^{1 to} R ² and R ^{5 to} R ⁷ are as defined in the general formula (I).

In another preferred embodiment of the invention, the compounds of formula (VII), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof The salt is a compound of formula (VII-A) or formula (VII-B), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutical product thereof. Is an acceptable salt:
In the formula: A, B, X, Y, R ^{1 to} R ² , R ⁸ and R ^b are as defined in the general formula (VII).

  In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein A, B and Y are selected from CH.

  In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein one of A, B and Y is selected from N and the other two are selected from -CH-.

In another embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Salt,
As, but not limited to:
Including:
R ³ and R ⁴ are as defined in general formula (I).

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein R ¹ is alkyl and haloalkyl, preferably tert-butyl, isopropyl,
, Selected from.

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein R ¹ is selected from cycloalkyl, the cycloalkyl is further substituted with haloalkyl, and R ¹ is preferably
It is.

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein R ² is selected from haloalkyl, preferably —CHF ₂ .

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein R ² is selected from haloalkyl and t is 0.

In another preferred embodiment of the invention, the compounds of formula (I), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein R ² is selected from halogen, preferably chlorine.

  In another preferred embodiment of the invention, the compounds of formula (III), or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Wherein t is 1.

Representative compounds of the present invention are not limited to these,
Or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

In other embodiments, the present invention provides:
Wherein R ^c is selected from hydroxy and halogen;
Ring P, Ring Q, A, B, Y, s, t and R ^{1 to} R ⁴ are as defined in general formula (I))
Subjecting a compound of general formula (IA) or a salt thereof to a condensation reaction with a compound of general formula (IB) under alkaline conditions to obtain a compound of formula (I), or Methods are provided for the preparation of their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

  Alkali reagents include organic bases and inorganic bases, such as, but not limited to, triethylamine, N, N-diisopropylethylamine, pyridine, sodium bis (trimethylsilyl) amide, n-butyllithium, potassium tert-butoxide and tetrabutylammonium bromide; such inorganic bases include, but are not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, sodium bicarbonate, potassium carbonate, Examples include potassium hydrogen carbonate or cesium carbonate; preferably triethylamine.

  Examples of the catalyst include, but are not limited to, Pd / C and Raney nickel.

  Examples of the condensing agent include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, O- (benzotriazole- 1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O- (benzotriazol-1-yl)- N, N, N ', N'-tetramethyluronium hexafluorophosphate, 2- (7-azo-benzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate Benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxy-tripyrrolidinyl-phosphonium hexafluorophosphate Eto, and the like.

In other embodiments, the present invention provides the following groups:
(Where:
R ³ is selected from hydrogen, alkyl, and heterocyclyl, wherein the alkyl is one or more groups selected from the group consisting of alkoxy and heterocyclyl, preferably C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or tetrahydrofuranyl. Optionally further substituted with
R ⁴ is selected from aryl and heteroaryl, which aryl or heteroaryl may be optionally further substituted with one or more groups selected from the group consisting of halogen and haloalkyl, which haloalkyl is preferably trifluoro R ⁴ is preferably phenyl, which is further substituted with one halogen or one haloalkyl.
t is 1;
However:
When the compound of general formula (IA) is in the following group:
R ³ is selected from hydrogen and alkyl, which alkyl is optionally further substituted with one or more groups selected from the group consisting of alkoxy and heterocyclyl;
R ⁴ is phenyl, which is further substituted with one haloalkyl, which is preferably trifluoromethyl; or
R ³ is heterocyclyl;
R ⁴ is phenyl, which is further substituted with one halogen or one haloalkyl. )
Providing a compound of formula (IA), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, consisting of:
.

Compounds of general formula (IA) are not limited to these:
Or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

In other embodiments, the invention provides compounds of Formula (IB), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, I will provide a:
(Where
R ^c is selected from hydroxy and halogen; and rings Q, R ¹ and R ² are as defined in general formula (I)).

Compounds of general formula (IB) are not limited to these:
Or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

  Another aspect of the present invention is a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof And a pharmaceutical composition containing a pharmaceutically acceptable carrier, diluent or excipient.

  Another aspect of the present invention is a compound of formula (I), or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease involving microsomal prostaglandin E synthase-1 (mPGES-1) , Mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

  Another aspect of the present invention is a compound of formula (I), or a tautomer, mesomer, racemate thereof, in the manufacture of a medicament for inhibiting microsomal prostaglandin E synthase-1 (mPGES-1) Bodies, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

  Another aspect of the present invention is a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, in the manufacture of a medicament for the treatment or prevention of a disease or disorder, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, wherein the disease or disorder is from inflammation, pain, cancer, diabetes and diabetic complications or neurodegenerative diseases, etc. The inflammation is selected from the group consisting of inflammation-related autoimmune diseases, skin diseases, lung diseases, visceral diseases, ear, nose, mouth and throat diseases or cardiovascular diseases; autoimmune diseases include arthritis , Osteoarthritis, juvenile arthritis, rheumatoid arthritis, ankylosing spondylitis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) or multiple sclerosis The skin disease includes dermatitis, eczema, psoriasis, burns or tissue trauma; the pulmonary disease includes asthma, chronic obstructive pulmonary disease (COPD)), or pulmonary fibrosis; Visceral diseases include inflammatory bowel disease, Crohn's disease, ulcerative colitis (IBS), gastrointestinal ulcer, cystitis, prostatitis, pancreatitis or nephritis; the ear, nose, mouth and throat diseases Include influenza, viral infection, bacterial infection, fever, rhinitis, sore throat, tonsillitis, conjunctivitis, iritis, scleritis or uveitis; such cardiovascular diseases include atherosclerosis, Thrombosis, stroke or coronary heart disease; such pain includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, labor pain, childbirth Pain, chronic Pain, persistent pain, peripheral neuropathic pain, central nervous pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury or a combination thereof; As prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, cutaneous T-cell lymphoma or cutaneous B-cell The diabetic and diabetic complications include diabetic vasculopathy, diabetic neuropathy or diabetic retinopathy; the neurodegenerative disease includes Alzheimer's disease or Parkinson's disease; The disease or disorder is preferably selected from inflammation and pain, more preferably osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondylitis or as listed above It is selected from pain associated with any one of the disease or disorder.

  Another aspect of the present invention relates to a method for treating a disease mediated by microsomal prostaglandin E synthase-1 (mPGES-1), the method comprising a compound of formula (I), or a tautomer, mesomer thereof A therapeutically effective amount of a racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, to a patient in need thereof Including doing.

  Another aspect of the present invention relates to a method of inhibiting microsomal prostaglandin E synthase-1 (mPGES-1), which method comprises a compound of formula (I), or a tautomer, mesomer, racemate thereof. Administering a therapeutically effective amount of an enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them to a patient in need thereof. Contains.

  Another aspect of the invention relates to a method of treating or preventing a disease or disorder, said method comprising a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or Administering a therapeutically effective amount of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them to a patient in need thereof; the disease or disorder is inflammation, Selected from the group consisting of pain, cancer, diabetes and diabetic complications or neurodegenerative diseases, including inflammation-related autoimmune diseases, skin diseases, lung diseases, visceral diseases, ear, nose, mouth and throat diseases Or autoimmune diseases include arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, ankylosing spondylitis, gout, rheumatic fever, bursitis, systemic lupus Todes (SLE) or multiple sclerosis, etc .; the skin diseases include dermatitis, eczema, psoriasis, burns or tissue trauma; the lung diseases include asthma, chronic obstructive pulmonary disease (COPD) ), Or pulmonary fibrosis; examples of the visceral disease include inflammatory bowel disease, Crohn's disease, ulcerative colitis (IBS)), gastrointestinal ulcer, cystitis, prostatitis, pancreatitis or nephritis The ear, nose, mouth and throat diseases include influenza, viral infection, bacterial infection, fever, rhinitis, sore throat, tonsillitis, conjunctivitis, iritis, scleritis or uveitis; Examples of the cardiovascular disease include atherosclerosis, thrombosis, stroke or coronary heart disease; examples of the pain include neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain Surgery Pain, postoperative pain, labor pain, childbirth pain, chronic pain, persistent pain, peripheral nervous pain, central nervous pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral Examples of the cancer include prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma Leukemia, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, etc .; the diabetic and diabetic complications include diabetic vasculopathy, diabetic neuropathy or diabetic retinopathy; The disease includes Alzheimer's disease or Parkinson's disease; the disease or disorder is preferably selected from inflammation and pain, more preferably osteoarthritis, rheumatoid arthritis Bursitis, is selected from ankylosing spondylitis or pain associated with one of the disease or disorder listed above.

  Another aspect of the present invention provides a compound of formula (I) or a tautomer thereof for use as a medicament for the treatment of a disease mediated by microsomal prostaglandin E synthase-1 (mPGES-1) The present invention relates to a sex form, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.

  Another aspect of the present invention provides a compound of formula (I), or a tautomer, mesomer for use as a drug for the inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

  Another aspect of the present invention is a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, for use as a medicament for the treatment or prevention of a disease or disorder. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them, wherein the disease or disorder is from inflammation, pain, cancer, diabetes and diabetic complications or neurodegenerative diseases, etc. The inflammation is selected from the group consisting of inflammation-related autoimmune diseases, skin diseases, lung diseases, visceral diseases, ear, nose, mouth and throat diseases or cardiovascular diseases; autoimmune diseases include arthritis , Osteoarthritis, juvenile arthritis, rheumatoid arthritis, ankylosing spondylitis, gout, rheumatic fever, bursitis, systemic lupus erythematosus (SLE) or multiple sclerosis The skin disease includes dermatitis, eczema, psoriasis, burns or tissue trauma; the pulmonary disease includes asthma, chronic obstructive pulmonary disease (COPD)), or pulmonary fibrosis; Visceral diseases include inflammatory bowel disease, Crohn's disease, ulcerative colitis (IBS), gastrointestinal ulcer, cystitis, prostatitis, pancreatitis or nephritis; the ear, nose, mouth and throat diseases Include influenza, viral infection, bacterial infection, fever, rhinitis, sore throat, tonsillitis, conjunctivitis, iritis, scleritis or uveitis; such cardiovascular diseases include atherosclerosis, Thrombosis, stroke or coronary heart disease; such pain includes neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, postoperative pain, labor pain, childbirth Pain, chronic Pain, persistent pain, peripheral neuropathic pain, central nervous pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury or a combination thereof; As prostate cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, melanoma, lymphoma, leukemia, cutaneous T-cell lymphoma or cutaneous B-cell The diabetic and diabetic complications include diabetic vasculopathy, diabetic neuropathy or diabetic retinopathy; the neurodegenerative disease includes Alzheimer's disease or Parkinson's disease; The disease or disorder is preferably selected from inflammation and pain, more preferably osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondylitis or as listed above It is selected from pain associated with any one of the disease or disorder.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, terms used in the specification and claims have the meanings set forth below.

“Alkyl” refers to a saturated aliphatic hydrocarbon group including C ₁ -C ₂₀ straight and branched chain groups, preferably alkyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Is an alkyl having Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n -Heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3 Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethyl Hexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2, 2-diethylhexyl and their branched isomers. More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Can be mentioned. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any substitutable position, and the substituent is preferably alkyl, alkenyl, alkynyl, alkyloxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, Cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxyl ester, -C (O) OR ⁵ ,- OC (O) OR ⁵ , -NHS (O) _m R ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O ) One or more groups independently selected from the group consisting of: NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ .

“Alkenyl” refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon double bond, eg, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl and the like, preferably C _2-10 alkenyl, more preferably C _2-6 alkenyl, and most preferably C _2-4 alkenyl. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxyl ester, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more groups independently selected from

“Alkynyl” refers to an alkyl as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl. Etc., preferably C _2-10 alkynyl, more preferably C _2-6 alkynyl, and most preferably C _2-4 alkynyl. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ ,- C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more groups selected independently from the group.

  "Cycloalkyl" is a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to Those having 10 carbon atoms, more preferably 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, preferably And cyclopropyl or cyclohexenyl. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a condensed ring or a bridged ring.

  A “spirocycloalkyl” is a 5-20 membered polycyclic group having a ring connected through one common carbon atom (referred to as a spiro atom), wherein one or more rings are one or more Although it may contain a double bond, none of the rings has a completely conjugated pi-electron system. Preferably spirocycloalkyl is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of common spiro atoms, spirocycloalkyl can be divided into a monospiro ring, a dispiro ring or a polyspiro ring, preferably a monospiro ring or a dispiro ring. More preferred spirocycloalkyl are 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monocyclic spirocycle. Representative examples of spirocycloalkyl include, but are not limited to, the following groups:

  A “fused cycloalkyl” is a 5- to 20-membered polycyclic hydrocarbon group in which each ring in the system shares a pair of adjacent carbon atoms with another ring, and one or more rings May contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably the fused cycloalkyl group is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, the fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic and polycyclic fused cycloalkyl, preferably bicyclic or tricyclic fused Cycloalkyl. More preferred fused cycloalkyl is 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyl include, but are not limited to, the following groups:

  “Bridged cycloalkyl” refers to a 5- to 20-membered polycyclic hydrocarbon group in which each two rings in the system share two unconnected carbon atoms. The ring may have one or more double bonds, but does not have a completely conjugated π-electron system. Preferably, the bridged cycloalkyl is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, the bridged cycloalkyl can be divided into bridged bicyclic rings, tricyclic rings, tetracyclic rings or polycyclic rings, preferably bicyclic rings, tricyclic rings or tetracycles. A cyclic ring-bridged cycloalkyl, more preferably a bicyclic ring or a tricyclic ring-bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following groups.

The cycloalkyl may be fused to an aryl, heteroaryl or heterocyclic alkyl ring and the ring attached to the parent structure is a cycloalkyl. Representative examples include, but are not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ ,- C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more groups selected independently from the group.

“Heterocyclyl” is a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group having N, O, and S (O) _m as ring atoms, m is one or more heteroatoms selected from the group consisting of 0 to 2, but there is no —O—O—, —O—S— or —S—S— in the ring, The remaining ring atoms are C. The heterocyclyl preferably has 3 to 12 ring atoms, 1 to 4 atoms are heteroatoms; more preferably 3 to 10 atoms; most preferably 5 to 6 ring atoms. Have. Representative examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like. Examples of polycyclic heterocyclyl include heterocyclyl having a spiro ring, a condensed ring or a bridged ring.

“Spiroheterocyclyl” is a 5-20 membered polycyclic heterocyclyl having a ring attached through one common carbon atom (referred to as a spiro atom), wherein the ring is N, O or Having one or more heteroatoms selected from the group consisting of S (O) _m (wherein m is an integer between 0 and 2), the remaining ring atoms being C, one or more This ring may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. Preferably, spiroheterocyclyl is 6-14 members, more preferably 7-10 members. Depending on the number of common spiro atoms, spiroheterocyclyl can be divided into mono-spiroheterocyclyl, di-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and di-spiroheterocyclyl. More preferably, the spiroheterocyclyl is a 4 member / 4 member, 4 member / 5 member, 4 member / 6 member, 5 member / 5 member, or 5 member / 6 member mono-spiroheterocyclyl. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups:

A “fused heterocyclyl” is a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares a pair of adjacent carbon atoms with another ring, and one or more rings are 1 Although it may contain more than one double bond, none of the rings has a completely conjugated pi-electron system, and the ring is N, O or S (O) _m as a ring atom, where m is It is one having at least one heteroatom selected from the group consisting of (which is an integer between 0 and 2) and the remaining ring atoms are C. Preferably the fused heterocyclyl is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic and polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl. is there. More preferred fused heterocyclyl is a 5/5/5 or 5/6/6 bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following groups:

“Bridged heterocyclyl” is a 5- to 14-membered polycyclic heterocyclylalkyl group in which each two rings in the system share two unconnected carbon atoms, and one or more such rings But may not have a completely conjugated π-electron system, and the ring may be N, O and S (O) _m (wherein m is between 0 and 2) as ring atoms. And the remaining ring atoms are C. The heteroatom is selected from the group consisting of: Preferably, the bridged heterocyclyl is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, the bridged heterocyclyl can be divided into a bicyclic ring, a tricyclic ring, a tetracyclic ring or a polycyclic ring-bridged heterocyclyl, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring. It is a cyclic ring bridged heterocyclyl, more preferably a bicyclic ring or a tricyclic ring bridged heterocyclyl. Representative examples of cross-linked heterocyclyl include, but are not limited to, the following groups.

The ring of heterocyclyl may be fused to an aryl, heteroaryl or cycloalkyl ring, but the ring attached to the parent structure is a heterocyclyl. Representative examples include, but are not limited to, the following groups:

Such.

Heterocyclyl may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, oxo, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ ,- C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more groups selected independently from the group.

“Aryl” refers to a 6-14 membered all-carbon monocyclic or polycyclic fused ring (“fused” ring system refers to a carbon atom pair in which each ring is adjacent to another ring in the system. Means a shared) and has a completely conjugated π-electron system. Aryl is preferably 6-10 members, more preferably phenyl and naphthyl, most preferably phenyl. The aryl may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl. Representative examples include, but are not limited to, the following groups:
The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ , -C ( O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more groups independently selected.

“Heteroaryl” refers to a 5- to 14-membered aryl having 1 to 4 heteroatoms containing oxygen, sulfur and nitrogen as ring atoms, and the other ring atoms being carbon. Heteroaryl is preferably 5-10 membered, more preferably 5 or 6 membered, most preferably furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, Such as pyrazolyl. The heteroaryl may be fused with an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl. Representative examples include, but are not limited to, the following groups:
The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocyclo Alkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ , -C ( O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ One or more independently selected groups

“Alkoxy” refers to both —O— (alkyl) and —O— (unsubstituted cycloalkyl) groups, where alkyl and cycloalkyl are as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxyl may be substituted or unsubstituted. If substituted, if substituted, the substituent is preferably alkyl, alkenyl, alkynyl, alkoxy, alkylthiol, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl , Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, -C (O) OR ⁵ , -OC (O) OR ⁵ , -NHS (O) _m R ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ One or more groups independently selected from the group consisting of R ⁷ .

“Haloalkyl” refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
“Hydroxy” refers to the group —OH.
“Hydroxyalkyl” refers to an alkyl group substituted with a hydroxy group, where alkyl is as defined above.
“Halogen” refers to fluorine, chlorine, bromine or iodine.
“Amino” refers to the group —NH ₂ .
“Cyano” refers to the group —CN.
“Nitro” refers to the —NO ₂ group.
“Benzyl” refers to the group —CH ₂ -phenyl.
An “oxo group” refers to a ═O group.
“Carboxyl” refers to the group —C (O) OH.
“Carboxylic acid ester” refers to —C (O) O (alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
“Amino protecting group” refers to a group that protects the amino with an easily removable group, thereby keeping the amino unchanged as the rest of the molecule reacts. Examples include, but are not limited to, formyl, alkylcarbonyl, alkoxycarbonyl, benzoyl, aralkylcarbonyl, aralkyloxycarbonyl, trityl, phthalyl, N, N-dimethylaminomethylene, substituted silyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro. The amino protecting group is preferably t-butyloxycarbonyl.

  “Arbitrary” or “arbitrary” means that the event or situation described subsequently does not necessarily have to occur. The description includes what happens or does not have to happen. For example, “heterocyclic group optionally substituted with alkyl” means that an alkyl group may or may not be present, and such a representation indicates that the heterocyclic group is substituted with alkyl. And the case where the heterocyclic group is not substituted with alkyl.

  “Substituted” refers to one or more hydrogen atoms within a group, preferably up to 5, more preferably 1-3 hydrogen atoms, each independently substituted with a corresponding number of substituents. . It goes without saying that substituents are only present at their chemically possible positions. One of ordinary skill in the art can determine whether replacement is possible through experience and theory without undue effort. For example, it is unstable if an amino or hydroxyl group with free hydrogen is bound to a carbon atom with an unsaturated bond (eg, an olefin).

A “pharmaceutical composition” refers to one or more compounds according to the present invention or other physiological / pharmaceutically acceptable salts or prodrugs thereof and other physiological / pharmaceutically acceptable carriers and excipients. A mixture of chemical components. The purpose of the pharmaceutical composition is to facilitate administration of the drug to the living body, thereby helping to absorb the active ingredient and realizing biological activity.
Here, m and R ^{5 to} R ⁷ are as defined in formula (I).

Method for Synthesizing the Compound of the Present Invention To achieve the object of the present invention, the present invention adopts the following synthetic technical scheme:
Method 1
In a process for preparing a compound of formula (I) of the present invention, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Including the following steps:
A compound of formula (Ia) is subjected to a reduction reaction in the presence of a catalyst to obtain a compound of formula (IA) or a salt thereof; a compound of formula (IA) or a salt thereof is converted to formula (IB) under alkaline conditions Condensation reaction with a compound of formula (I) to obtain a compound of formula (I);
Wherein R ^c is hydroxy or halogen; Ring P, Ring Q, A, B, Y, s, t and R ^{1 to} R ⁴ are as defined in Formula (I).

Method 2
In a process for producing a compound of formula (III), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, Including steps:
The compound of formula (IIIa) is subjected to a coupling reaction with the compound of formula (IIIb) in the presence of a catalyst to obtain a compound of formula (IIIc), and the compound of formula (IIIc) is subjected to a reduction reaction in the presence of a catalyst. To obtain a compound of formula (III) or a salt thereof; a compound of formula (IIIA) or a salt thereof is further subjected to a condensation reaction with a compound of formula (IIIB) under alkaline conditions to obtain a compound of formula (III) ;
Wherein R ^c is hydroxy or halogen; R ^d is halogen, preferably bromine or iodine, and E, G and W are each independently CR ^a , NR ^b , N, O or S And A, B, X, Y, t, R ¹ , R ² and R ⁴ are as defined in formula (I).
The method for synthesizing the compounds of formula (IV) and formula (V) is similar or similar to the method for synthesizing the compound of formula (III).

Method 3
In a process for preparing a compound of formula (VI), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, Including steps:
The compound of formula (VIa) is subjected to a coupling reaction with the compound of formula (IIIb) in the presence of a catalyst to obtain a compound of formula (VIb), and the compound of formula (VIb) is subjected to a reduction reaction in the presence of a catalyst. To obtain a compound of formula (VIA) or a salt thereof; a compound of formula (VIA) or a salt thereof is further subjected to a condensation reaction with a compound of formula (VIB) under alkaline conditions to obtain a compound of formula (VI) ;
Wherein R ^c is hydroxy or halogen; R ^d is halogen, preferably bromine or iodine, and A, B, X, Y, t, R ¹ , R ² and R ⁴ are of formula (I And R ^b is as defined in formula (IV).

Method 4
The compound of formula (VIa) is subjected to a coupling reaction with the compound of formula (VIb) in the presence of a catalyst to obtain a compound of formula (Vb), and the compound of formula (Vb) is subjected to a reduction reaction in the presence of a catalyst. To obtain a compound of formula (VA) or a salt thereof; a compound of formula (VA) or a salt thereof is further subjected to a condensation reaction with a compound of formula (VB) under alkaline conditions to obtain a compound of formula (VII) ;
Wherein R ^c is hydroxy or halogen; R ^d is halogen, preferably bromine or iodine, and A, B, X, Y, R ¹ and R ² are as defined in formula (I) R ^b is as defined in formula (IV) and R ⁸ is as defined in formula (VII).

  In the above synthesis technique, the alkaline conditions are supplied by an organic base or an inorganic base, and the organic base includes, but is not limited to, triethylamine, N, N-diisopropylethylamine, pyridine, sodium bis (trimethylsilyl) amide, n-butyllithium, potassium tert-butoxide or tetrabutylammonium bromide; and inorganic bases include but are not limited to lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, Examples thereof include sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, and cesium carbonate, and triethylamine is preferable.

  Catalysts include, but are not limited to, Pd / C, Raney nickel, tetrakis (triphenylphosphine) palladium, palladium chloride, palladium acetate, 1,1'-bis (diphenylphosphino) ferrocene-palladium (II) dichloride and tris. (Dibenzylideneacetone) dipalladium.

  Examples of the condensing agent include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, O- (benzotriazole- 1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N, N, N' , N'-Tetramethyluronium hexafluorophosphate, 2- (7-azo-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, benzotriazole-1- Ile-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate, or benzotriazol-1-yl-oxy-tripyrrolidinyl-phosphonium hexafluorophosphate Is mentioned.

The invention is further illustrated based on the following specific examples. These examples are merely to illustrate the invention and do not limit the scope of the invention.
The experimental methods in the following examples, in which specific conditions are not shown, can be carried out according to conventional conditions or conditions recommended by the raw material or product manufacturer. Experimental reagents whose specific origins have not been shown are conventional reagents that can be generally purchased from the market.

The structure of the compound was identified by nuclear magnetic resonance (NMR) and / or mass spectrum (MS). NMR was measured with Bruker AVANCE-400. The solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDC ₁₃ ) and deuterated methanol (CD ₃ OD). The internal standard was tetramethylsilane (TMS). NMR chemical shift (δ) was shown in 10 ⁻⁶ (ppm).
MS was measured with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
High performance liquid chromatography (HPLC) was measured with an Agilent 1200DAD high pressure liquid chromatography device (Sunfire C18 150 x 4.6 mm chromatography column) and Waters 2695-2996 high pressure liquid chromatography device (Gimini C18 150 x 4.6 mm chromatography column). .
The average enzyme inhibition and IC ₅₀ values were determined by NovoStar ELISA (BMG Co., Germany).
For thin layer silica gel chromatography (TLC), Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The plate size used in TLC was 0.15 mm to 0.2 mm, and the plate size used in product purification was 0.4 mm to 0.5 mm.
In column chromatography, Yantai Huanghai 200-300 mesh silica gel was used as a carrier.
Known starting materials of the present invention can be prepared by known synthetic methods in the prior art or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. or Dari Chemical Company.
Unless otherwise stated, reactions were performed under a nitrogen or argon atmosphere.
“Nitrogen atmosphere” or “argon atmosphere” means that the reaction flask is equipped with a 1 L nitrogen or argon balloon.
“Hydrogen atmosphere” means that the reaction flask is equipped with a 1 L hydrogen balloon.
The high-pressure hydrogenation reaction was performed using a Parr 3916EKX type hydrogenation device and a QL-500 type hydrogen generator or an HC2-SS type hydrogenation device.
In the hydrogenation reaction, the reaction system was usually evacuated and filled with hydrogen, and this operation was repeated three times.
A microwave reactor of type CEM Discover-S 908860 was used for the microwave reaction.
Unless otherwise specified, the solution used in the reaction refers to an aqueous solution.
Unless otherwise stated, the reaction temperature in the reaction is room temperature. The temperature range is 20 ° C to 30 ° C.
The progress of the reaction is monitored by thin layer chromatography (TLC), and the elution system includes A: dichloromethane and methanol, B: n-hexane and ethyl acetate, C: petroleum ether and ethyl acetate, and D: acetone. . The volume ratio of the solvent can be adjusted according to the polarity of the compound.
Elution systems for compound purification by column chromatography and thin layer chromatography are: A: dichloromethane and methanol, B: n-hexane and ethyl acetate, C: n-hexane and acetone, D: n-hexane and E: Contains ethyl acetate. The volume ratio of the solvent can be adjusted depending on the polarity of the compound, and sometimes a small amount of an alkaline reagent such as triethylamine or an acidic reagent can be added.

2- (Difluoromethyl) -N- (1-ethyl-2 (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
Ethyl 5-cyano-2- (difluoromethyl) nicotinic acid
3-Dimethylaminoacrylonitrile 1a (865 mg, 9.0 mmol, prepared according to the method disclosed in Pharma Chemica, 2010, 2 (3), 178-186) was dissolved in 20 mL of N, N-dimethylformamide. And heated to 65 ° C. To this solution was added N, N-dimethyl of ethyl 2- (ethoxymethylene) -4,4-difluoro-3-oxo-butyric acid 1b (2.0 g, 9.0 mmol, prepared according to the method disclosed in patent application WO2012025469). 5 mL of a formamide solution was added dropwise and stirred for 1 hour. Next, ammonium acetate (1.1 g, 14.0 mmol) was added to the reaction solution, and the mixture was further stirred for 16 hours. The reaction solution was concentrated under reduced pressure, 100 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system C to give a pale yellow oil, ie the title compound ethyl 5-cyano-2- (difluoromethyl) nicotinic acid 1c (606 mg, 30%). Obtained.
MS m / z (ESI): 227.1 [M + 1]

Process 2
Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride Ethyl 5-cyano-2- (difluoromethyl) nicotinic acid 1c (606 mg, 2.7 mmol) is dissolved in 15 mL of ethanol and concentrated hydrochloric acid is added. (1.0 mL, 37%) and Pd / C (180 mg, 10%) were added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through Ceratom, and the filtrate was concentrated under reduced pressure to give the title compound ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride 1d (709 mg, 99%) as a yellow solid. .
MS m / z (ESI): 231.1 [M + 1]

Process 3
Ethyl 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinate ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride 1d (709 mg, 2.7 mmol) Was dissolved in 50 mL of dichloromethane and N, N-diisopropylethylamine (1.9 mL, 10.6 mmol) was added. After the addition was completed, a dichloromethane solution (0.7 M, 5 mL) of isobutyryl chloride was added dropwise to the reaction mixture, and the mixture was stirred for 2 hours. The reaction mixture was washed sequentially with water (50 mL) and a saturated solution of sodium bicarbonate (50 mL). The organic layer was concentrated under reduced pressure to give a pale yellow solid, i.e., the title compound ethyl 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinate 1e (790 mg, 99%). Obtained.
MS m / z (ESI): 301.1 [M + 1]

Process 4
2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid ethyl 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinate
1e (790 mg, 2.6 mmol) was dissolved in 10 mL of 1,4-dioxane, and 5 mL of water and lithium hydroxide hydrate (291 mg, 6.9 mmol) were added. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. 5 mL of water was added to the residue, and the pH was adjusted to 2 with 5M hydrochloric acid. A large amount of solid precipitated and was filtered. The filtrate was extracted with ethyl acetate (50 mL × 3). The organic layers were combined and concentrated under reduced pressure. The residue is combined with the above filter cake, washed with water and dried to give a pale yellow solid, i.e. the title compound 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (420 mg, 56%).
MS m / z (ESI): 273.1 [M + 1]

Process 5
2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinoyl chloride
2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (150 mg, 0.55 mmol) was dissolved in 5 mL of dichloromethane and 1 drop of N, N-dimethylformamide and chloride was added. Thionyl (197 mg, 1.65 mmol) was added. After the addition was complete, the reaction mixture was stirred for 2 hours. This was concentrated under reduced pressure to obtain a pale yellow oil, 1 g (160 mg) of the title compound 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinoyl chloride. This was used in the next step without further purification.

Step 6
1-ethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole
1-ethyl-5-nitro-1H-indole 1h (500 mg, 2.63 mmol, prepared according to the method disclosed in Bioorganic & Medicinal Chemistry, 2005, 13 (10), 3531-3541) in 5 mL N , N-dimethylacetamide, 4-iodotrifluorotoluene 1i (790 mg, 2.92 mmol), triphenylphosphine (140 mg, 0.53 mmol), palladium acetate (30 mg, 0.13 mmol) and cesium acetate (1.6 g , 5.21 mmol) was added sequentially. After the addition was complete, the resulting mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was then concentrated under reduced pressure. 50 mL of ethyl acetate was added to the residue, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 1-ethyl-5-nitro-2- (4- (trifluoromethyl) as a yellow solid. Phenyl) -1H-indole 1j (130 mg, 14.8%) was obtained.
MS m / z (ESI): 335.1 [M + 1]

Step 7
1-Ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole
1-ethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 1j (130 mg, 0.39 mmol) in 10 mL of tetrahydrofuran and methanol mixture (V: V = 1: 1) And Raney nickel (30 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through ceratom and the filtrate was concentrated under reduced pressure to give a pale yellow solid, i.e., the title compound 1-ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 1k. Crude product (120 mg) was obtained. This was used in the next step without purification.
MS m / z (ESI): 305.1 [M + 1]

Process 8
2- (Difluoromethyl) -N- (1-ethyl-2 (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide
1-Ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 1k (120 mg, 0.39 mmol) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (0.10 mL, 0.78 mmol) was dissolved. In addition, a tetrahydrofuran solution of 1 g (160 mg, 0.55 mmol) of 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinoyl chloride was added dropwise. The reaction mixture was stirred for 1 hour. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (difluoromethyl) -N- (1-ethyl-2 (4- (trifluoromethyl) phenyl)- 1H-Indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide 1 (25 mg, 11.5%) was obtained.
MS m / z (ESI): 559.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.68 (s, 1H), 8.46 (t, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.93 -7.86 (d, 2H), 7.85-7.78 (d, 2H), 7.61-7.55 (d, 1H), 7.47-7.42 (d, 1H), 7.19 (t, 1H), 6.70 (s, 1H), 4.47 -4.39 (d, 2H), 4.31-4.20 (m, 2H), 2.49-2.41 (m, 1H), 1.21 (t, 3H), 1.09-1.03 (d, 6H).

2-Chloro-N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) -benzamide

Process 1
2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride
2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoic acid 2a (500 mg, 1.86 mmol, prepared according to the method disclosed in patent application "WO2012025469") in 10 mL of dichloromethane And thionyl chloride (0.4 mL, 5.58 mmol) was added dropwise, and 1 drop of N, N-dimethylformamide was added. After the addition was complete, the reaction mixture was stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure to give a yellow oil, ie the title compound 2-chloro-5-((2,2-dimethylpropanoylamino) -methyl) benzoyl chloride 2b (550 mg). This was used in the next step without further purification.

Process 2
2-Chloro-N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide
1-Ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 1k (90 mg, 0.27 mmol) was dissolved in 5 mL of tetrahydrofuran and triethylamine (75 μL, 0.54 mmol) was dissolved. In addition, a tetrahydrofuran solution of 2 mL of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (77 mg, 0.27 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred for 1 hour and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to obtain a pale yellow solid, ie the title compound 2-chloro-N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -1H-Indol-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide 2 (45 mg, 30%) was obtained.
MS m / z (ESI): 557.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.40 (s, 1H), 8.18 (t, 1H), 8.10 (s, 1H), 7.92-7.87 (d, 2H), 7.84-7.79 (d, 2H), 7.58-7.53 (d, 1H), 7.52-7.48 (d, 1H), 7.47-7.41 (m, 2H), 7.36-7.30 (d, 1H), 6.69 (s, 1H), 4.34-4.29 ( d, 2H), 4.29-4.21 (m, 2H), 1.21 (t, 3H), 1.13 (s, 9H).

2-Chloro-N- (2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) -benzamide

Process 1
3-((4-Fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine
2-Amino-3-bromo-5-nitro-pyridine 3b (1.0 g, 4.6 mmol), 1-ethynyl-4-fluoro-benzene 3a (1.24 g, 10.3 mmol), bis (triphenylphosphine) palladium (II) Chloride (0.25 g, 0.35 mmol), copper iodine (7 mg, 0.35 mmol) and triethylamine (0.7 mL, 4.6 mmol) were added to 20 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours under an argon atmosphere. The reaction mixture was filtered through ceratom and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C, and the crude product of the title compound 3-((4-fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine 3c (1.7 g) as a brown solid Got. This was used in the next step without further purification.
MS m / z (ESI): 256.0 [M-1]

Process 2
2- (4-Fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine
3-((4-Fluorophenyl) ethynyl) -5-nitro-pyridin-2-amine 3c (1.7 g, 4.6 mmol) and potassium tert-butoxide (1.0 g, 9.2 mmol) in 20 mL N, N-dimethyl Dissolved in formamide. The reaction mixture was heated to 70 ° C. and stirred for 16 hours. The reaction solution was concentrated under reduced pressure. 200 mL of water was added to the residue, followed by filtration with ceratom. The filter cake was purified by silica gel column chromatography using elution system C, and 20 mL of dichloromethane was added and filtered. The residue was dried to obtain a crude product (564 mg) of the title compound 2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 3d as a yellow solid. This was used in the next step without further purification.

Process 3
2- (4-Fluorophenyl) -5-amino-1H-pyrrolo (2,3-b) pyridine
2- (4-Fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 3d (64 mg, 0.25 mmol) in 10 mL of tetrahydrofuran and methanol mixture (V: V = 1: 1) After dissolution, Raney nickel (30 mg) was added. The reaction mixture was stirred for 1 hour under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to give a brown oil (60 mg) of the title compound 2- (4-fluorophenyl) -5-amino-1H-pyrrolo (2,3-b) pyridine 3e. It was. This was used in the next step without further purification.
MS m / z (ESI): 226.1 [M-1]

Process 4
2-Chloro-N- (2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide
2- (4-Fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pyridine 3e (60 mg, 0.25 mmol) was dissolved in 8 mL of tetrahydrofuran, and triethylamine (0.43 mL, 0.31 mmol) was dissolved. In addition, a tetrahydrofuran solution of 5 mL of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (220 mg, 0.76 mmol) was added dropwise. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to obtain a pale yellow solid, ie the title compound 2-chloro-N- (2- (4-fluorophenyl) -1H-pyrrolo [2,3 -b] pyridin-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide 3 (5 mg, 4.2% over 2 steps) was obtained.
MS m / z (ESI): 479.4 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.16 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.65-7.56 (m, 1H), 7.55-7.46 (m, 2H), 7.48-7.36 (m, 2H), 7.27-7.16 (m, 3H), 6.41 (s, 1H), 5.15 (m, 1H), 4.26-4.21 (m, 2H), 1.13 (s, 9H) .

2-Chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) 5-((2,2-dimethylpropanoylamino) methyl ) -Benzamide

Process 1
1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine
2- (4-Fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 3d (60 mg, 0.23 mmol), iodomethane (40 μL, 0.47 mmol) and cesium carbonate (150 mg, 0.47 mmol) ) Was added to 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours, 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 4). The organic layers were combined, washed with a saturated solution of sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give the title compound 1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 4a as a yellow solid Of crude product (70 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 286.1 [M + 1]

Process 2
1-ethyl-2- (4-fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pyridine
1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 4a (70 mg, 0.23 mmol) was added to 10 mL of a mixture of tetrahydrofuran and methanol (V: V = After being dissolved in 1: 1), Raney nickel (20 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to give a pale yellow solid, ie crude product of the title compound 1-ethyl-2- (4-fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pyridine 4b (60 mg). This was used in the next step without further purification.
MS m / z (ESI): 256.2 [M + 1]

Process 3
2-Chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H-pyrrolo [2,3-b] pyridin-5-yl) -5-((2,2-dimethylpropanoylamino) Methyl) -benzamide
1-Ethyl-2- (4-fluorophenyl) -5-amino-1H-pyrrolo [2,3-b] pyridine 4b (60 mg, 0.23 mmol) was dissolved in 5 mL of tetrahydrofuran and triethylamine (65 μL, 0.47 mmol) was added, and 5 mL of a tetrahydrofuran solution of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (220 mg, 0.76 mmol) was added dropwise. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2-chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H-pyrrolo [2, 3-b] pyridin-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) -benzamide 4 (5 mg, 4.2% over 3 steps) was obtained.
MS m / z (ESI): 507.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.15 (s, 1H), 8.05 (s, 1H), 7.93 (s, 1H), 7.66-7.56 (m, 1H), 7.55-7.48 (m, 2H), 7.48-7.38 (m, 2H), 7.27-7.17 (m, 3H), 6.56 (s, 1H), 4.34-4.28 (d, 2H), 4.29-4.20 (m, 2H), 1.23 (t, 3H), 1.12 (s, 9H).

2- (Difluoromethyl) -N- (1-ethyl-2- (4-fluorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-indole 5b
1-ethyl-3- (4-fluorophenyl) -5-nitro-1H-indole 5c
1-Ethyl-5-nitro-1H-indole 1h (1.64 g, 6.17 mmol) was dissolved in 20 mL of N, N-dimethylacetamide and then 1-fluoro-4-iodo-benzene 5a (4.65 g, 21.0 mmol). ), Triphenylphosphine (360 mg, 1.36 mmol), palladium acetate (70 mg, 0.31 mmol) and cesium acetate (4.0 g, 12.3 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system C, both of which were the yellow solid title compound, 1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-indole 5b (0.51 g, 29.1%) and 1-ethyl-3- (4-fluorophenyl) -5-nitro-1H-indole 5c (125 mg, 7.1%).
5b: MS m / z (ESI): 285.0 [M + 1]
5c: MS m / z (ESI): 285.1 [M + 1]

Process 2
1-ethyl-2- (4-fluorophenyl) -5-amino-1H-indole
After dissolving 1-ethyl-2- (4-fluorophenyl) -5-nitro-1H-indole 5b (35 mg, 0.12 mmol) in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Raney nickel (10 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to give a crude product (31 mg) of the title compound 1-ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d as a yellow solid. This was used in the next step without further purification.
MS m / z (ESI): 255.2 [M + 1]

Process 3
2- (Difluoromethyl) -N- (1-ethyl-2- (4-fluorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide
1-Ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (31 mg, 0.12 mmol) was dissolved in 5 mL of acetonitrile, triethylamine (31 μL, 0.22 mmol) was added, and 5 An acetonitrile solution of 1 g (32 mg, 0.11 mmol) of 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinoyl chloride was added dropwise. The reaction mixture was stirred for 1 hour and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -N- (1-ethyl-2- (4 -Fluorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide 5 (35 mg, 62.5%) was obtained.
MS m / z (ESI): 509.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.70 (s, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.63-7.54 (m, 2H), 7.46-7.51 (d, 2H), 7.44-7.39 (d, 2H), 7.32-7.25 (m, 2H), 7.12 (t, 1H), 6.51 (s, 1H), 5.36 (t, 1H), 4.53 (s, 2H), 4.30 -4.21 (m, 2H), 1.27 (t, 3H), 1.20-1.14 (d, 6H).

2-Bromo-N- (1-ethyl-3- (4-fluorophenyl) -1Hindol-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide

Process 1
2-Bromo-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride
2-Bromo 5-((2,2-dimethylpropanoylamino) methyl) benzoic acid 6a (500 mg, 1.59 mmol, prepared according to the method disclosed in patent application "US20120157506") in 10 mL dichloromethane After dissolution, thionyl chloride (0.4 mL, 4.78 mmol) and 1 drop of N, N-dimethylformamide were added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure to give a pale yellow solid, i.e. crude product of the title compound 2-bromo-5-((2,2-dimethylpropanoylamino) -methyl) benzoyl chloride 6b ( 530 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 331.1 [M-1]

Process 2
1-ethyl-3- (4-fluorophenyl) -5-amino-1H-indole
After dissolving 1-ethyl-3- (4-fluorophenyl) -5-nitro-1H-indole 5c (110 mg, 0.39 mmol) in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Raney nickel (20 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to obtain a crude product (100 mg) of the title compound 1-ethyl-3- (4-fluorophenyl) -5-amino-1H-indole 6c as a gray solid. This was used in the next step without further purification.
MS m / z (ESI): 255.2 [M + 1]

Process 3
2-Bromo-N- (1-ethyl-3- (4-fluorophenyl) -1H-indol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) -benzamide
Dissolve 1-ethyl-3- (4-fluorophenyl) -5-amino-1H-indole 6c (100 mg, 0.39 mmol) in 5 mL of tetrahydrofuran, add triethylamine (63 μL, 0.45 mmol), and add 5 mL A solution of 2-bromo-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 6b (50 mg, 0.15 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2-bromo-N- (1-ethyl-3- (4-fluorophenyl) -1H-indole-5- Yl) -5-((2,2-dimethylpropanoylamino) methyl) -benzamide 6 (15 mg, 18.2%).
MS m / z (ESI): 551.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.17 (s, 1H), 7.99 (s, 1H), 7.66-7.56 (m, 4H), 7.55-7.50 (m, 3H), 7.43-7.37 ( m, 1H), 7.25-7.19 (m, 1H), 7.15 (t, 1H), 6.28 (s, 1H), 4.46-4.36 (d, 2H), 4.30-4.20 (m, 2H), 1.55 (t, 3H), 1.25 (s, 9H).

2-Bromo-N- (1-ethyl-2- (4-fluorophenyl) -1H-indol-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide
1-Ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (30 mg, 0.12 mmol) was dissolved in 5 mL of tetrahydrofuran, triethylamine (63 μL, 0.45 mmol) was added, and 5 A tetrahydrofuran solution of mL of 2-bromo-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 6b (50 mg, 0.15 mmol) was added dropwise. The reaction mixture was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2-bromo-N- (1-ethyl-2- (4-fluorophenyl) -1H-indole-5- Yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide 7 (5 mg, 10.4%) was obtained.
MS m / z (ESI): 551.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.00 (s, 1H), 7.90 (s, 1H), 7.65-7.56 (m, 2H), 7.54-7.48 (m, 2H), 7.47-7.38 ( m, 2H), 7.28-7.17 (m, 3H), 6.52 (s, 1H), 6.22 (s, 1H), 4.50-4.40 (d, 2H), 4.25-4.16 (m, 2H), 1.33 (t, 3H), 1.27 (s, 9H).

2-Chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H-indol-5-yl) 5-((2,2-dimethylpropanoylamino) methyl) benzamide
1-ethyl-2- (4-fluorophenyl) -5-amino-1H-indole 5d (38 mg, 0.15 mmol), 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoic acid 2a (40 mg, 0.15 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (57 mg, 0.3 mmol), 1-hydroxybenzotriazole (2 mg, 0.015 mmol) and N, N-diisopropyl Ethylamine (38 mg, 0.3 mmol) was dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2-chloro-N- (1-ethyl-2- (4-fluorophenyl) -1H-indole-5- Yl) 5-((2,2-dimethylpropanoylamino) methyl) -benzamide 8 (5 mg, 6.7%) was obtained.
MS m / z (ESI): 506.0 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 7.95-7.90 (d, 2H), 7.82-7.77 (d, 2H), 7.57-7.47 (d, 2H), 7.48-7.45 (m, 2H), 7.30-7.22 (m, 1H), 6.72 (s, 1H), 4.40-4.36 (d, 2H), 4.33-4.29 ( m, 2H), 1.21 (t, 3H), 1.12 (s, 9H)

2- (Difluoromethyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1Hindol-5-yl) 5-((2-methylpropanoylamino) methyl) -nicotinamide

Process 1
1-Methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 9b
1-Methyl-5-nitro-1H-indole 9a (1.0 g, 5.7 mmol) is dissolved in 40 mL of N, N-dimethylacetamide, 4-iodotrifluorobenzene 1i (1.7 g, 6.2 mmol), triphenyl Phosphine (300 mg, 1.4 mmol), palladium acetate (130 mg, 0.57 mmol) and cesium acetate (2.2 g, 1.4 mmol) were added sequentially. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. 50 mL of ethyl acetate was added to the residue, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B, and the title compound 1-methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 9b (350 mg, 350 mg, 19.4%) was obtained.
MS m / z (ESI): 321.1 [M + 1]

Process 2
1-Methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole
1-Methyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 9b (350 mg, 1.1 mmol) was dissolved in 10 mL of tetrahydrofuran, and then Raney nickel (35 mg) was added. . The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture is then filtered through Ceratom and the filtrate is concentrated under reduced pressure to give a brown oil, ie the title compound 1-methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole. 9c crude product (300 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 291.2 [M + 1]

Process 3
2- (Difluoromethyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) 5-((2-methylpropanoylamino) methyl) -nicotine Amide
1-methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 9c (150 mg, 0.52 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino ) Methyl) nicotinic acid 1f (141 mg, 0.52 mmol), O-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (250 mg, 0.78 mmol) and N, N- Diisopropylethylamine (100 mg, 0.78 mmol) was dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 75 ^° C. and stirred for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -N- (1-methyl-2) as a brown solid. -(4- (Trifluoromethyl) phenyl) -1H-indol-5-yl) 5-((2-methylpropanoylamino) methyl) -nicotinamide 9 (10 mg, 2.0%) was obtained.
MS m / z (ESI): 545.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.68 (s, 1H), 8.50-8.47 (m, 1H), 8.09 (s, 1H), 8.03 (s, 1H) , 7.90-7.85 (m, 4H), 7.56-7.54 (m, 1H), 7.48-7.45 (m, 1H), 7.28-7.20 (m, 1H), 6.75 (s, 1H), 4.44-4.42 (d, 2H), 3.80 (s, 3H), 2.47-2.46 (m, 1H), 1.07-1.05 (d, 6H)

2- (Difluoromethyl) -N- (1-ethyl-2- (4-chlorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
1-Ethyl-2- (4-chlorophenyl) -5-nitro-1H-indole
1-Ethyl-5-nitro-1H-indole 1h (439 mg, 2.3 mmol) was dissolved in 5 mL of N, N-dimethylacetamide and 1-chloro-4-iodo-benzene 10a (500 mg, 2.1 mmol) , Triphenylphosphine (110 mg, 0.42 mmol), palladium acetate (24 mg, 0.11 mmol) and cesium acetate (806 mg, 4.2 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and then stirred for 18 hours under an argon atmosphere. The reaction mixture was filtered. 150 mL of ethyl acetate was added to the filtrate, followed by washing with water (20 mL × 1). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give the title compound 1-ethyl-2- (4-chlorophenyl) -5-nitro-1H-indole 10b (80 mg, 12.7%) as a yellow solid. It was.

Process 2
1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole
After dissolving 1-ethyl-2- (4-chlorophenyl) -5-nitro-1H-indole 10b (80 mg, 0.27 mmol) in 20 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel (10 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to obtain a crude product (72 mg) of the title compound 1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole 10c as a gray solid. This was used in the next step without further purification.
MS m / z (ESI): 271.1 [M + 1]

Process 3
2- (Difluoromethyl) -N- (1-ethyl-2- (4-chlorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide
1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole 10c (50 mg, 0.18 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (55 mg, 0.18 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (70 mg, 0.37 mmol) and 1-hydroxybenzotriazole (25 mg, 0.18 mmol) in 3 mL of N, N -Dissolved sequentially in dimethylformamide. The reaction mixture was heated to 40 ^° C. and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -N- (1-ethyl-2- ( 4-Chlorophenyl) -1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide 10 (20 mg, 27.8%) was obtained.
MS m / z (ESI): 525.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.57 (s, 1H), 8.65 (s, 1H), 8.44 (t, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.59 (s, 2H), 7.52 (d, 1H), 7.41 (d, 1H), 7.39 (s, 1H), 6.57 (s, 1H), 4.42 (d, 2H), 4.21 (d, 2H), 3.89 ( s, 1H), 1.25 (d, 3H), 1.22 (t, 2H), 1.03 (d, 6H).

2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide

Process 1
2- (4-Fluorophenyl) -1-methyl-5-nitro-1H-indole
1-Methyl-5-nitro-1H-indole 9a (0.8 g, 4.5 mmol) was dissolved in 10 mL of N, N-dimethylacetamide and then 1-fluoro-4-iodo-benzene 5a (1.12 g, 5.0 mmol). ), Triphenylphosphine (238 mg, 0.9 mmol), palladium acetate (51 mg, 0.23 mmol) and cesium acetate (1.7 g, 0.91 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and then stirred for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system C to give the title compound 2- (4-fluorophenyl) -1-methyl-5-nitro-1H-indole 11a (130 mg, 10.7%) as a yellow solid. Obtained.
MS m / z (ESI): 271.1 [M + 1]

Process 2
2- (4-Fluorophenyl) -1-methyl-5-amino-1H-indole
After 2- (4-fluorophenyl) -1-methyl-5-nitro-1H-indole 11a (130 mg, 0.48 mmol) was dissolved in 16 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Raney nickel (15 mg) was added. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to obtain a crude product (130 mg) of the title compound 2- (4-fluorophenyl) -1-methyl-5-amino-1H-indole 11b as a yellow solid. This was used in the next step without further purification.

Process 3
2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
2- (4-Fluorophenyl) -1-methyl-5-amino-1H-indole 11b (70 mg 0.29 mmol) was dissolved in 20 mL of tetrahydrofuran, triethylamine (85 μL, 0.60 mmol) was added, and 5 mL Of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (83 mg, 0.29 mmol) in tetrahydrofuran was added dropwise. The reaction mixture was stirred for 2 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2-chloro-N- (2- (4-fluorophenyl) -1- Methyl-1H-indol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 11 (40 mg, 28.0%) was obtained.
MS m / z (ESI): 492.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.01 (s, 1H), 7.91 (s, 1H), 7.65-7.56 (m, 2H), 7.54-7.49 (m, 2H), 7.48-7.38 ( m, 2H), 7.28-7.17 (m, 3H), 6.52 (s, 1H), 6.22 (s, 1H), 4.25-4.16 (m, 2H), 3.83 (t, 3H), 1.27 (s, 9H) .

2- (Difluoromethyl) -N- (1-ethyl-1H-indol-5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide
1-ethyl-1H-indole-5-amine 12a (50 mg, 0.31 mmol, prepared according to the method disclosed in Bioorganic & Medicinal Chemistry, 2005, 13 (10), 3531-3541), 2- (difluoro Methyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (70 mg, 0.26 mmol), O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium Tetrafluoroborate (124 mg, 0.39 mmol) and N, N-diisopropylethylamine (100 mg, 0.78 mmol) were sequentially dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 75 ^° C. and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -N- (1-ethyl-1H-indole) as a brown solid. -5-yl) -5-((2-methylpropanoylamino) methyl) nicotinamide 12 (20 mg, 18.9%) was obtained.
MS m / z (ESI): 415.1 [(M + 1])
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.53 (s, 1H), 8.67 (s, 1H), 8.46 (t, 1H), 7.99 (s, 2H), 7.50-7.44 (d, 1H) , 7.42-7.34 (m, 2H), 7.18 (t, 1H), 6.46-6.40 (d, 1H), 4.47-4.39 (d, 2H), 4.25-4.15 (m, 2H), 2.49-2.41 (m, 1H), 1.36 (t, 3H), 1.10-1.01 (d, 6H).

N- (2- (4-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-indole
1-Methyl-5-nitro-1H-indole 9a (3.30 g, 18.7 mmol) was dissolved in 20 mL of N, N-dimethylacetamide and then 1-chloro-4-iodo-benzene 10a (4.96 g, 20.8 mmol ), Triphenylphosphine (982 mg, 3.75 mmol), palladium acetate (210 mg, 0.94 mmol) and cesium acetate (7.20 g, 3.75 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and then stirred for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with a saturated solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using elution system C to give the title compound 2- (4-chlorophenyl) -1-methyl-5-nitro-1H-indole 13a ( 270 mg, 5.0%).

Process 2
2- (4-Chlorophenyl) -1-methyl-5-amino-1H-indole
After dissolving 2- (4-chlorophenyl) -1-methyl-5-nitro-1H-indole 13a (80 mg, 0.28 mmol) in 20 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel (8 mg) was added. The reaction mixture was stirred for 1 hour under hydrogen atmosphere. The reaction mixture was filtered through ceratom and the filtrate was concentrated under reduced pressure to give a slightly off-white solid, i.e. crude crude of the title compound 2- (4-chlorophenyl) -1-methyl-5-amino-1H-indole 13b. The product (72 mg) was obtained. This was used in the next step without further purification.

Process 3
N- (2- (4-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide
2- (4-Chlorophenyl) -1-methyl-5-amino-1H-indole 13b (72 mg, 0.28 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 5 mL of 1f (77 mg, 0.28 mmol), 1-ethyl- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (81 mg, 0.42 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol) Were sequentially dissolved in N, N-dimethylformamide. The reaction mixture was heated to 40 ^° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give a solid. To this was added 20 mL of dichloromethane, stirred for 20 minutes, and the title compound N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl)- 5-((2-Methylpropanoylamino) methyl) nicotinamide 13 (20 mg, 14.0%) was obtained.
MS m / z (ESI): 511.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 8.68 (s, 1H), 8.45 (s, 1H), 8.04 (d, 2H), 7.62 (dd, 4H), 7.47 (dd, 2H), 7.20 (t, 1H), 6.64 (s, 1H), 4.43 (d, 2H), 3.76 (s, 3H), 2.46 (m, 1H), 1.06 (d, 6H).

N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide

Process 1
Ethyl 2- (difluoromethyl) -5-(((2-fluoro-2-methylpropanoyl) amino) methyl) nicotinate ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride 1d (2.18 g , 8.20 mmol) in 20 mL of N, N-dimethylformamide, then 2-fluoroisobutyric acid (1.04 g, 9.83 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.36 g , 12.30 mmol), 1-hydroxybenzotriazole (1.66 g, 12.30 mmol) and triethylamine (7 mL, 49.2 mmol) were added sequentially. After the reaction mixture was stirred for 16 hours, 100 mL of ethyl acetate and 50 mL of water were added. The organic layer was concentrated under reduced pressure. The residue was purified by TLC using elution system A and the title compound ethyl 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinate 14a (1.6 g , 61.3%).
MS m / z (ESI): 319.1 [M + 1]

Process 2
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid
After 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinate 14a (1.6 g, 5.03 mmol) was dissolved in 50 mL of 1,4-dioxane, 25 mL of water and lithium hydroxide hydrate (529 mg, 12.6 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction mixture was then concentrated under reduced pressure, 5 mL of water was added to the residue, and the pH was adjusted to 3 with 5M hydrochloric acid. A large amount of solid precipitated from the reaction solution and was filtered. The filtrate was extracted with ethyl acetate (50 mL × 3). The organic layers were combined and concentrated under reduced pressure. The residue was combined with the above filter cake, washed with water, and the title compound 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (500 mg, 34.2%).
MS m / z (ESI): 291.1 [M + 1]

Process 3
N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide
1-ethyl-2- (4-chlorophenyl) -5-amino-1H-indole 10c (100 mg, 0.37 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) Amino) methyl) nicotinic acid 14b (107 mg, 0.37 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (142 mg, 0.74 mmol) and 1-hydroxybenzotriazole (191 mg, 1.48 mmol) Were sequentially dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 14 (40 mg, 19.9%) was obtained.
MS m / z (ESI): 543.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.87 (s, 1H), 8.69 (m, 1H), 8.04-8.02 (m, 2H), 7.60-7.58 (m, 4H), 7.54-7.53 (m, 1H), 7.43-7.42 (m, 1H), 7.19 (t, 1H), 6.59 (s, 1H), 4.48-4.46 (m, 2H), 4.24-4.19 (m, 2H), 1.54-1.48 (d, 6H), 1.26-1.15 (m, 3H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1H-indole -5-yl) nicotinamide
1-methyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 9c (50 mg, 0.17 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2 -Methyl-propanoyl) amino) methyl) nicotinic acid 14b (50 mg, 0.17 mmol), 1-ethyl- (3-dimethylaminopropyl) -3carbodiimide hydrochloride (55 mg, 0.29 mmol), 1-hydroxybenzotriazole ( 2.3 mg, 0.017 mmol) and N, N-diisopropylethylamine (44 mg, 0.34 mmol) were sequentially dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to obtain a pale yellow solid, ie the title compound 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino ) Methyl) -N- (1-methyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 15 (4 mg, 4.2%) was obtained.
MS m / z (ESI): 563.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.90-7.85 (m, 4H) , 7.56-7.54 (m, 1H), 7.47-7.44 (m, 1H), 7.20 (s, 1H), 6.75 (s, 1H), 4.48-4.46 (m, 2H), 3.80 (s, 3H), 1.54 -1.48 (d, 6H).

2-Chloro-N- (2- (4-chlorophenyl) indazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide

Process 1
2- (4-Chlorophenyl) -5-nitro-indazole Sodium nitrate (1.6 g, 19.2 mmol) was added to 10 mL of sulfuric acid in an ice-water bath. Next, 2- (4-chlorophenyl) -2H-indazole 16a (2.2 g, 9.6 mmol) was added in several portions. The reaction mixture was heated to 70 ^° C. and stirred for 1 hour. The reaction mixture was poured into 30 mL ice-water and the pH was adjusted to> 7 with a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 2- (4-chlorophenyl) -5-nitro-2H-indazole 16b (500 mg, 19.2) as a yellow solid. %).
MS m / z (ESI): 274.0 [M + 1]

Process 2
2- (4-Chlorophenyl) -5-amino-indazole
2- (4-Chlorophenyl) -5-nitro-indazole 16b (500 mg, 1.8 mmol) was dissolved in 20 mL of tetrahydrofuran, and then Raney nickel (50 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Ceratom and the filter cake was washed with ethyl acetate (5 mL × 3). The filtrate was concentrated under reduced pressure to give a crude product (200 mg, 45%) of the title compound 2- (4-chlorophenyl) -5-amino-indazole 16c as a brown solid.
MS m / z (ESI): 244.1 [M + 1]

Process 3
2-Chloro-N- (2- (4-chlorophenyl) -2H-indazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
2- (4-Chlorophenyl) -5-amino-indazole 16c (200 mg, 0.37 mmol), 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (300 mg, 1.04 mmol ) And N, N-diisopropylethylamine (300 mg, 2.32 mmol) were sequentially dissolved in 10 mL of dichloromethane. The resulting mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to obtain a pale yellow solid, ie the title compound 2-chloro-N- (2- (4-chlorophenyl) -2H-indazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 16 (5 mg, 1.3%) was obtained.
MS m / z (ESI): 495.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.56 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.19-8.11 (m, 3H), 7.73-7.66 (m, 3H), 7.51 (m, 1H), 7.45-7.44 (m, 2H), 7.36-7.34 (m, 1H), 4.31-4.30 (m, 2H), 1.14 (s, 9H)

2- (Difluoromethyl) -N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-(((2-fluoro-2-methyl-propanoyl ) Amino) methyl) nicotinamide
1-ethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 1k (105 mg, 0.34 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2 -Methyl-propanoyl) amino) methyl) nicotinic acid 14b (100 mg, 0.34 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (97 mg, 0.51 mmol), 1-hydroxybenzotriazole (4.6 mg, 0.034 mmol) and N, N-diisopropylethylamine (88 mg, 0.68 mmol) were sequentially dissolved in 5 mL of N, N-dimethylformamide. The resulting mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (difluoromethyl) -N- (1-ethyl-2- (4- (trifluoromethyl) phenyl) as a yellow solid -1H-Indol-5-yl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 17 (20 mg, 25.5%) was obtained.
MS m / z (ESI): 577.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.90 -7.88 (m, 2H), 7.82-7.80 (m, 2H), 7.58-7.56 (m, 1H), 7.45-7.43 (m, 1H), 7.32 (t, 1H), 6.69 (s, 1H), 4.47 -4.46 (m, 2H), 4.28-4.26 (m, 2H), 1.53-1.48 (d, 6H), 1.22-1.09 (m, 3H).

N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide
2- (4-Chlorophenyl) -1-methyl-5-amino-1H-indole 13b (45 mg, 0.18 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) Amino) methyl) nicotinic acid 14b (51 mg, 0.18 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (51 mg, 0.26 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol) and Triethylamine (71 mg, 0.70 mmol) was sequentially dissolved in 5 mL of N, N-dimethylformamide. The resulting mixture was stirred for 3 hours, then concentrated under reduced pressure, and the residue was purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound N- (2- (4 -Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 18 (43 mg, 46.2%).
MS m / z (ESI): 529.1 [M + 1]
1H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.04 (d, 2H), 7.62 (dd, 4H), 7.47 ( dd, 2H), 7.20 (t, 1H), 6.64 (s, 1H), 4.47 (d, 2H), 3.76 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H).

N- (2- (2-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide

Process 1
2- (2-Chlorophenyl) -1-ethyl-5-nitro-1H-indole
1-Ethyl-5-nitro-1H-indole 1h (1.0 g, 5.3 mmol) was dissolved in 10 mL of N, N-dimethylacetamide and then 1-chloro-2-iodo-benzene 19a (1.25 g, 5.3 mmol). ), Triphenylphosphine (300 mg, 1.1 mmol), palladium acetate (120 mg, 0.53 mmol) and cesium acetate (2.1 g, 11 mmol) were sequentially added. The reaction mixture was heated to 140 ^° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system B to give the title compound 2- (2-chlorophenyl) -1-ethyl-5-nitro-1H as a yellow solid. -Indole 19b (300 mg, 18.9%) was obtained.
MS m / z (ESI): 301.3 [M + 1]

Process 2
2- (2-Chlorophenyl) -1-ethyl-1H-indole-5-amine
After 2- (2-chlorophenyl) -1-ethyl-5-nitro-1H-indole 19b (300 mg, 1.0 mmol) was dissolved in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel (50 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to obtain a crude product (270 mg) of the title compound 2- (2-chlorophenyl) -1-ethyl-1H-indole-5-amine 19c as a yellow solid. This was used in the next step without further purification.
MS m / z (ESI): 271.1 [M + 1]

Process 3
N- (2- (2-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide
2- (2-Chlorophenyl) -1-ethyl-1H-indole-5-amine 19c (80 mg, 0.30 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) Amino) methyl) nicotinic acid 14b (86 mg, 0.30 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (115 mg, 0.60 mmol), 1-hydroxybenzotriazole (40 mg, 0.30 mmol) and Triethylamine (118 mg, 1.17 mmol) was dissolved sequentially in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 40 ^° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound N- (2- (2-chlorophenyl) -1-ethyl-1H- Indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 19 (10 mg, 14.3%) was obtained.
MS m / z (ESI): 543.9 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 8.87 (s, 1H), 8.68 (s, 1H), 8.02 (d, 2H), 7.65 (d, 1H), 7.52 -7.49 (m, 3H), 7.42 (d, 1H), 6.48 (s, 1H), 4.46 (d, 2H), 3.99-3.97 (m, 2H), 2.88 (s, 1H), 2.73 (s, 1H ), 1.53 (s, 3H), 1.46 (s, 3H), 1.09 (t, 3H)

N- (2- (3-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide

Process 1
2- (3-Chlorophenyl) -1-ethyl-5-nitro-1H-indole
1-Ethyl-5-nitro-1H-indole 1h (1.0 g, 5.3 mmol) was dissolved in 10 mL of N, N-dimethylacetamide and then 1-chloro-3-iodo-benzene 20a (1.4 g, 5.8 mmol ), Triphenylphosphine (276 mg, 1.1 mmol), palladium acetate (119 mg, 0.53 mmol) and cesium acetate (2.0 g, 11 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture is then concentrated under reduced pressure and the residue is purified by silica gel column chromatography using elution system C to give the title compound 2- (3-chlorophenyl) -1-ethyl-5-nitro-1H- as a yellow solid. Indole 20b (120 mg, 7.6%) was obtained.
MS m / z (ESI): 301.1 [M + 1]

Process 2
2- (3-Chlorophenyl) -1-ethyl-1H-indole-5-amine
After 2- (3-chlorophenyl) -1-ethyl-5-nitro-1H-indole 20b (50 mg, 0.17 mmol) was dissolved in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel (5 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a red oil, crude product (45 mg) of the title compound 2- (3-chlorophenyl) -1-ethyl-1H-indole-5-amine 20c. This was used in the next step without further purification.
MS m / z (ESI): 271.1 [M + 1]

Process 3
N- (2- (3-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide
2- (3-Chlorophenyl) -1-ethyl-1H-indole-5-amine 20c (45 mg, 0.17 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) Amino) methyl) nicotinic acid 14b (49 mg, 0.17 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol) and Triethylamine (68 mg, 0.66 mmol) was sequentially dissolved in 5 mL of N, N-dimethylformamide. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to give a slightly off-white solid, ie the title compound N- (2- (3-chlorophenyl) -1-ethyl-1H-indole- 5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 20 (45 mg, 50% over 2 steps) was obtained.
MS m / z (ESI): 543.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.03 (d, 2H), 7.57-7.55 (m, 6H) , 7.43 (t, 1H), 7.19 (s, 1H), 6.64 (d, 2H), 4.49-4.47 (m, 2H), 1.54 (s, 3H), 1.49 (s, 3H), 1.19 (t, 3H ).

N- (2- (4-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl Nicotinamide

Process 1
Ethyl 2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinate Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride 1d (4.0 g, 13.2 mmol) was dissolved in 50 mL of N, N-dimethylformamide, then 1- (trifluoromethyl) cyclopropane-1-carboxylic acid 21a (2.03 g, 13.2 mmol), 1-ethyl- (3- Dimethylaminopropyl) carbodiimide hydrochloride (5.07 g, 26.4 mmol), 1-hydroxybenzotriazole (178 mg, 1.32 mmol) and triethylamine (5.3 g, 52.8 mmol) were added sequentially. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was washed with ethyl acetate (50 mL) and water (50 mL) and dried to a brown oil, ie the title compound ethyl 2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropane The crude product (4.83 g) of carbonyl) amino) methyl) nicotinate 21b was obtained. This was used in the next step without further purification.
MS m / z (ESI): 367.1 [M + 1]

Process 2
2- (Difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinic acid ethyl 2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclo Propanecarbonyl) amino) methyl) nicotinate 21b (4.83 g, 13.2 mmol) was dissolved in 150 mL of a mixture of 1,4-dioxane and water (V: V = 2: 1), followed by lithium hydroxide hydrate ( 1.38 g, 33.0 mmol) was added. The reaction mixture was stirred for 1 hour. Ethanol was removed under reduced pressure and the pH of the residue was adjusted to 4-5 with 6M hydrochloric acid. A large amount of solid precipitated out, and 100 mL of ethyl acetate was added thereto. The solid was filtered and dried to give the title compound 2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) -methyl) nicotinic acid 21c (2.0 g, 2 44.8%) was obtained in the process.
MS m / z (ESI): 339.1 [M + 1]

Process 3
N- (2- (4-Chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl Nicotinamide
2- (4-Chlorophenyl) -1-methyl-5-amino-1H-indole 13b (45 mg, 0.17 mmol), 2- (difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl ) Amino) methyl) nicotinic acid 21c (59 mg, 0.17 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (51 mg, 0.26 mmol), 1-hydroxybenzotriazole (24 mg, 0.17 mmol) And triethylamine (71 mg, 0.70 mmol) were sequentially dissolved in 5 mL of N, N-dimethylformamide. The resulting mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound N- (2- (4-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (Difluoromethyl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) nicotinamide 21 (20 mg, 20%) was obtained.
MS m / z (ESI): 577.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.67 (s, 1H), 8.59-8.57 (m, 1H), 8.03 (d, 2H), 7.62 (dd, 4H) , 7.47 (dd, 2H), 7.19 (t, 1H), 6.64 (s, 1H), 4.46 (d, 2H), 3.76 (s, 3H), 1.28-1.26 (m, 4H).

2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide

Process 1
5-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole
4- (Trifluoromethyl) benzoic acid 22a (2.0 g, 10.5 mmol) was dissolved in 14 mL of polyphosphoric acid, and then 2-amino-4-nitrophenol (1.62 g, 10.5 mmol) was added. The reaction mixture was heated to 120 ^° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature and then poured into 500 mL of water. Sodium hydroxy was added to this solution in several portions, and the pH was adjusted to 7, followed by extraction with ethyl acetate (500 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 5-nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole 22b (1.5 g) as a brown solid. This was used in the next step without further purification.

Process 2
2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine
5-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole 22b (170 mg, 0.55 mmol) was dissolved in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Later, Raney nickel (20 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a crude product (150 mg) of the title compound 2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c as a brown solid. This was used in the next step without further purification.
MS m / z (ESI): 279.1 [M + 1]

Process 3
2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide
2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 10 mL of tetrahydrofuran, and trifluoroacetic acid (54 μL, 0.39 mmol) was added. In addition, a tetrahydrofuran solution of 2 mL of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (52 mg, 0.18 mmol) was added dropwise. The resulting mixture was stirred for 1 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give a solid. To this was added 10 mL of ethyl acetate and filtered. The filter cake is dried and pale yellow solid, i.e. the title compound 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] Oxazol-5-yl) benzamide 22 (15 mg, 15.3% over 2 steps) was obtained.
MS m / z (ESI): 530.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.41 (s, 1H), 8.19 (t, 1H), 8.11 (s, 1H), 7.91-7.87 (d, 2H), 7.83-7.79 (d, 2H), 7.59-7.53 (d, 2H), 7.53-7.48 (d, 2H), 7.48-7.41 (m, 1H), 4.29-4.22 (m, 2H), 1.13 (s, 9H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazole-5- Il) Nicotinamide
2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 10 mL of N, N-dimethylformamide and then 2- (difluoromethyl) -5-(((2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (52 mg, 0.18 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (75 mg, 0.39 mmol), 1-hydroxybenzotriazole (2.4 mg, 0.02 mmol) and triethylamine (73 mg, 0.72 mmol) were added sequentially. The resulting mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give a solid. To this was added 10 mL of diethyl ether and filtered. The filter cake was dried and pale yellow solid, i.e. the title compound 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- ( Trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 23 (10 mg, 10.1%) was obtained.
MS m / z (ESI): 551.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.69 (s, 1H), 8.45 (t, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.92 -7.86 (d, 2H), 7.85-7.79 (d, 2H), 7.61-7.56 (d, 1H), 7.46-7.42 (d, 1H), 7.20 (t, 1H), 4.31-4.21 (m, 2H) , 2.49-2.40 (m, 1H), 1.09-1.02 (d, 6H).

2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) -2H-indol-5-yl) nicotinamide

Process 1
N- (2-nitrobenzyl) -4- (trifluoromethyl) aniline
4-Aminobenzotrifluoride 24a (2.35 g, 14.56 mmol) was dissolved in 50 mL of 1,2-dichloromethane, and then 2-nitrobenzaldehyde 24b (2.0 g, 13.23 mmol) was added. The resulting mixture was stirred for 0.5 hour, sodium triacetoxyborohydride (5.6 g, 26.46 mmol) was added, and the mixture was further stirred for 16 hours. To the reaction mixture was added 100 mL dichloromethane and 100 mL water. The organic layer is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system C to give a yellow oil, ie the title compound N- (2-nitrobenzyl) -4- (trifluoro Methyl) aniline 24c (3.5 g, 89.4%) was obtained.
MS m / z (ESI): 297.1 [M + 1]

Process 2
2- (4- (Trifluoromethyl) phenyl) -2H-indazole zinc powder (1.73 g, 27.04 mmol) was added to 50 mL of tetrahydrofuran followed by titanium tetrachloride (2.57 g, 13.55 mmol). The reaction mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction solution was cooled to room temperature and the pH was adjusted to 8 with triethylamine. N- (2-nitrobenzyl) -4- (trifluoromethyl) aniline 24c (1.0 g, 3.38 mmol) was dissolved in 20 mL of tetrahydrofuran and then added to the obtained mixture. The reaction mixture was continuously stirred for another 30 minutes, and then the pH was adjusted to 3 with 6M hydrochloric acid. This solution was extracted with dichloromethane (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 2- (4- (trifluoromethyl) phenyl) -2H-indazole 24d ( 100 mg, 11.3%) was obtained.
MS m / z (ESI): 263.1 [M + 1]

Process 3
5-Nitro-2- (4- (trifluoromethyl) phenyl) -2H-indazole Sodium nitrate (29 mg, 0,67 mmol) was added to 1 mL of sulfuric acid in an ice bath, and then 2- ( 4- (Trifluoromethyl) phenyl) -2H-indazole 24d (50 mg, 0.19 mmol) was added in several portions. The reaction mixture was heated to 70 ^° C. and stirred for 1 hour. The reaction mixture was poured into 30 mL ice-water and the pH was adjusted to> 7. This solution was extracted with ethyl acetate (40 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 5-nitro-2- (4- (trifluoromethyl) phenyl) -2H as a yellow solid. -Indazole 24e (30 mg, 25.6%) was obtained.
MS m / z (ESI): 308.1 [M + 1]

Process 4
2- (4- (Trifluoromethyl) phenyl) -2H-indazole-5-amine
After dissolving 5-nitro-2- (4- (trifluoromethyl) phenyl) -2H-indazole 24e (30 mg, 0.098 mmol) in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Raney nickel (3 mg) was added. The reaction mixture was stirred for 1 hour under hydrogen atmosphere. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a pale yellow solid, ie the crude product (27 mg) of the title compound 2- (4- (trifluoromethyl) phenyl) -2H-indazol-5-amine 24f. This was used in the next step without further purification.
MS m / z (ESI): 278.1 [M + 1]

Process 5
2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide
2- (4- (Trifluoromethyl) phenyl) -2H-indazol-5-amine 24f (27 mg, 0.098 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotine Acid 1f (27 mg, 0.10 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (29 mg, 0.15 mmol) and 1-hydroxybenzotriazole (14 mg, 0.10 mmol) in 5 mL N Were added sequentially to N-dimethylformamide. The resulting mixture was heated to 40 ^° C. and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give a solid. 20 mL of dichloromethane was added to this solid and stirred for 20 minutes. The mixture was filtered and the filter cake was washed with dichloromethane (5 mL × 3) and dried to give the title compound 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N as a white solid. -(2- (4- (Trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide 24 (27 mg, 50.9%) was obtained.
MS m / z (ESI): 532.1 [M + 1]
1H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 9.25 (s, 1H), 8.70 (s, 1H), 8.47 (t, 1H), 8.38-8.33 (m, 3H), 8.08-7.97 (m, 3H), 7.76 (d, 1H), 7.49 (d, 1H), 7.19 (t, 1H), 4.44 (d, 2H), 2.49-2.41 (m, 1H), 1.06 (d, 6H).

2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) benzamide

Process 1
6-Nitro-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one
4-Aminobenzotrifluoride 24a (193 mg, 1.2 mmol) was dissolved in 3 mL of ethanol, then methyl 2- (bromomethyl) -5-nitro-benzoic acid 25a (274 mg, 1.0 mmol) and N, N- Diisopropylethylamine (258 mg, 2.0 mmol) was added. The reaction mixture was heated to 110 ^° C. and stirred for 16 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was dried to give the title compound 6-nitro-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25b (70 mg, 21.7%) as a yellow solid.
MS m / z (ESI): 321.0 [M-1]

Process 2
6-Amino-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one
6-Nitro-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25b (70 mg, 0.098 mmol) dissolved in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) After that, Raney nickel (7 mg) was added. The reaction mixture was stirred for 1 hour under a hydrogen atmosphere and then filtered through Ceratom. The filtrate was concentrated under reduced pressure to give a crude product (64 mg) of the title compound 6-amino-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25c as a white solid. This was used in the next step without further purification.
MS m / z (ESI): 293.1 (M + 1)

Process 3
2- (4- (Trifluoromethyl) phenyl) isoindoline-5-amine
6-amino-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25c (64 mg, 0,22 mmol) After dissolving in 10 mL of tetrahydrofuran, lithium aluminum hydride (51 mg, 1.32 mmol) was added. The reaction mixture was heated to 65 ^° C. and stirred for 16 hours. To the reaction mixture was added 0.1 mL sodium hydroxide solution (15%) and 0.4 mL water, followed by magnesium sulfate. This was stirred for an additional 5 minutes. The mixture was filtered and extracted with ethyl acetate. The organic layer is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (4- (trifluoromethyl) phenyl) isoindoline-5- Amine 25d (11 mg, 18.0%) was obtained.
MS m / z (ESI): 279.1 [M + 1]

Process 4
2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) benzamide
2- (4- (Trifluoromethyl) phenyl) isoindoline-5-amine 25d (11 mg, 0.04 mmol), 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoic acid 2a ( 11 mg, 0.04 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (12 mg, 0.06 mmol), 1-hydroxybenzotriazole (6 mg, 0.04 mmol) and triethylamine (17 mg, 0.16 mmol) Were sequentially added to 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) -N- (2- ( 4- (Trifluoromethyl) phenyl) isoindoline-5-yl) benzamide 25 (6 mg, 28.6%) was obtained.
MS m / z (ESI): 530.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.18 (t, 1H), 7.89 (s, 1H), 7.60-7.50 (m, 4H), 7.42-7.34 (m, 3H), 6.80 (d, 2H), 4.68 (d, 4H), 4.30 (d, 2H), 1.14 (s, 9H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotine Amide
2- (4- (Trifluoromethyl) phenyl) isoindoline-5-amine 25d (63 mg, 0.23 mmol) was dissolved in 5 mL of N, N-dimethylformamide to give 2- (difluoromethyl) -5- ( ((2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (66 mg, 0.23 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (67 mg, 0.35 mmol), 1 -Hydroxybenzotriazole (27 mg, 0.23 mmol) and triethylamine (93 mg, 0.92 mmol) were added sequentially. The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) as a white solid -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotinamide 26 (50 mg, 39.7%) was obtained.
MS m / z (ESI): 551.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 8.87 (s, 1H), 8.70 (s, 1H), 8.00 (s, 1H), 7.87 (s, 1H), 7.57 (d, 3H), 7.42 (d, 1H), 7.16 (t, 1H), 6.80 (d, 2H), 4.69 (d, 4H), 4.66 (d, 2H), 1.53 (s, 3H), 1.48 ( s, 3H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (2-methoxyethyl) -2- (4- (trifluoromethyl) phenyl ) -1H-Indol-5-yl) nicotinamide

Process 1
1- (2-methoxyethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole
1- (2-methoxyethyl) -5-nitro-1H-indole 27a (2.2 g, 10 mmol, prepared according to the method disclosed in patent application “US20090076275”) with 10 mL of N, N-dimethylacetamide 1-iodo-4- (trifluoromethyl) benzene 1i (2.7 g, 10 mmol), triphenylphosphine (564 mg, 2.0 mmol), palladium acetate (225 mg, 1.0 mmol) and cesium acetate ( 3.8 g, 20 mmol) was added sequentially. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was washed with ethyl acetate (5 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 1- (2-methoxyethyl-5-nitro-2- (4- (trifluoromethyl) as a yellow solid. ) Phenyl) -1H-indole 27b (300 mg, 8.2%) was obtained.
MS m / z (ESI): 365.1 (M + 1)

Process 2
1- (2-methoxyethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole
1- (2-methoxyethyl-5-nitro-2- (4- (trifluoromethyl) phenyl) -1H-indole 27b (100 mg, 0.27 mmol) was mixed with 20 mL of tetrahydrofuran and methanol (V: V = After addition of Raney nickel (10 mg), the reaction mixture was stirred under a hydrogen atmosphere for 2 hours, then the reaction mixture was filtered through ceratom and the filter cake was diluted with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give a crude oil of the title compound 1- (2-methoxyethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 27c. A product (90 mg) was obtained, which was used in the next step without further purification.
MS m / z (ESI): 335.1 [M + 1]

Process 3
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (2-methoxyethyl) -2- (4- (trifluoromethyl) phenyl ) -1H-Indol-5-yl) nicotinamide
1- (2-methoxyethyl-5-amino-2- (4- (trifluoromethyl) phenyl) -1H-indole 27c (150 mg, 0.44 mmol), 2- (difluoromethyl) -5-(((2 -Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (128 mg, 0.44 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (169 mg, 0.88 mmol), 1-hydroxybenzo Triazole (6 mg, 0.04 mmol) and triethylamine (178 mg, 1.76 mmol) were sequentially dissolved in 10 mL of N, N-dimethylacetamide, the reaction mixture was heated to 75 ^° C. and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -5-(((2-fluoro-2 -Methyl-propanoyl) amino) methyl) -N- (1- (2-methoxyethyl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl ) Nicotinamide 27 (60 mg, 22.4%) was obtained.
MS m / z (ESI): 607.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ10.624 (s, 1H), 8.879 (s, 1H), 8.692 (s, 1H), 8.021-8.062 (m, 2H), 7.871-7.921 (m , 4H), 7.592-7.614 (m, 1H), 7.421-7.438 (m, 1H), 7.192-7.416 (m, 1H), 6.689 (s, 1H), 4.376-4.815 (m, 4H), 3.548-3.575 (m, 2H), 3.058-3.575 (s, 3H), 1.443-1.541 (d, 6H)

2- (Difluoromethyl) -N- (1-ethyl-2- (3- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-(((2-fluoro-2-methyl-propanoyl ) Amino) methyl) -nicotinamide

Process 1
1-ethyl-5-nitro-2- (3- (trifluoromethyl) phenyl) -1H-indole
1-Ethyl-5-nitro-1H-indole 1h (500 mg, 2.63 mmol) was dissolved in 5 mL of N, N-dimethylacetamide and 1-iodo-3- (trifluoromethyl) benzene 28a (860 mg , 3.16 mmol), triphenylphosphine (140 mg, 0.53 mmol), palladium acetate (119 mg, 0.13 mmol) and cesium acetate (2.0 g, 11 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 16 hours under an argon atmosphere. 40 mL of water was added to the reaction solution, and extracted with ethyl acetate (40 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using elution system C to give the title compound 1-ethyl-5-nitro-2- (3- (trifluoromethyl) phenyl)- 1H-indole 28b (100 mg, 11.4%) was obtained.
MS m / z (ESI): 335.1 [M + 1]

Process 2
1-Ethyl-5-amino-2- (3- (trifluoromethyl) phenyl) -1H-indole
1-ethyl-5-nitro-2- (3- (trifluoromethyl) phenyl) -1H-indole 28b (110 mg, 0.33 mmol) in 8 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) After dissolution, Raney nickel (30 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture is then filtered through Ceratom and the filtrate is concentrated under reduced pressure to give a pale yellow solid, ie the title compound 1-ethyl-5-amino-2- (3- (trifluoromethyl) phenyl) -1H-indole. 28c crude product (100 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 305.1 [M + 1]

Process 3
2- (Difluoromethyl) -N- (1-ethyl-2- (3- (trifluoromethyl) phenyl) -1H-indol-5-yl) -5-(((2-fluoro-2-methyl-propanoyl ) Amino) methyl) nicotinamide
1-ethyl-5-amino-2- (3- (trifluoromethyl) phenyl) -1H-indole 28c (50 mg, 0.16 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2 -Methyl-propanoyl) amino) methyl) nicotinic acid 14b (50 mg, 0.16 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (70 mg, 0.33 mmol) and 1-hydroxybenzotriazole (25 mg , 0.16 mmol) was added sequentially to 3 mL of N, N-dimethylacetamide. The reaction mixture was heated to 40 ^° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -N- (1-ethyl-2- ( 3- (Trifluoromethyl) phenyl) -1H-indol-5-yl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 28 (20 mg, 21.1%) was obtained. It was.
MS m / z (ESI): 575.5 [M-1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.59 (s, 1H), 8.85 (s, 1H), 8.67 (s, 1H), 8.03 (d, 2H), 7.85-7.83 (m, 1H) , 7.81-7.79 (m, 2H), 7.56 (d, 1H), 7.44 (d, 1H), 6.68 (s, 1H), 4.46 (d, 2H), 4.22-4.18 (m, 2H), 2.87 (s , 1H), 2.72 (s, 1H), 1.52 (s, 3H), 1.46 (s, 3H), 1.22 (t, 3H)

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide

Process 1
5-Nitro-2- (4- (trifluoromethyl) phenyl) benzofuran
4- (Trifluoromethyl) (pinacorboryl) benzene 29a (170 mg, 0.62 mmol) was dissolved in 6 mL of a mixture of 1,4-dioxane and water (V: V = 5: 1) and then 2-bromo- 5-Nitro-benzofuran 29b (100 mg, 0.43 mmol, prepared according to the method disclosed in European Journal of Organic Chemistry, 2013, 2013 (9), 1644-1648), [1,1'-bis (diphenyl Phosphino) ferrocene] dichloropalladium (II) (30 mg, 0.04 mmol) and sodium carbonate (88 mg, 0.83 mmol) were added. The reaction mixture was heated to 100 ° C. and stirred for 16 hours under an argon atmosphere. 50 mL of dichloromethane was added to the reaction solution, and filtered through Ceratom. Concentrate the filtrate under reduced pressure and purify the residue by thin layer chromatography (TLC) using elution system C to obtain a pale yellow solid, ie the title compound 5-nitro-2- (4- (trifluoromethyl) phenyl. ) Benzofuran 29c (80 mg) was obtained. This was used in the next step without further purification.

Process 2
5-Amino-2- (4- (trifluoromethyl) phenyl) benzofuran
5-Nitro-2- (4- (trifluoromethyl) phenyl) benzofuran 29c (40 mg, 0.13 mmol) was dissolved in 10 mL of a mixture of tetrahydrofuran and water (V: V = 1: 1) and then Raney nickel ( 40 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom and the filtrate was concentrated under reduced pressure to give a pale yellow solid, i.e., the title compound 5-amino-2- (4- (trifluoromethyl) phenyl) benzofuran 29d (36 mg). It was. This was used in the next step without further purification.
MS m / z (ESI): 278.2 [M + 1]

Process 3
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide
5-Amino-2- (4- (trifluoromethyl) phenyl) benzofuran 29d (33 mg, 0.12 mmol), 2- (difluoromethyl) -5-((((2-fluoro-2-methyl-propanoyl) amino) 3 mL of methyl) nicotinic acid 14b (35 mg, 0.12 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (45 mg, 0.24 mmol) and 1-hydroxybenzotriazole (16 mg, 0.12 mmol) Of N, N-dimethylacetamide was added sequentially. The reaction mixture was heated to 40 ^° C. and stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to afford the title compound 2- (difluoromethyl) -5-(((2-fluoro -2-Methyl-propanoyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide 29 (20 mg, 30.3%) was obtained.
MS m / z (ESI): 550.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.7 (s, 1H), 8.71 (s, 1H), 8.49 (t, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.93 -7.88 (m, 2H), 7.86-7.80 (m, 2H), 7.61-7.56 (m, 1H), 7.46-7.42 (m, 1H), 7.31-7.01 (m, 1H), 7.15 (s, 1H) , 4.44-4.38 (m, 2H), 1.55-1.49 (m, 6H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) Phenyl) -1H-indol-5-yl) nicotinamide

Process 1
5-Nitro- (1-tetrahydrofuran-3-yl) -1H-indole After 5-nitroindole 30a (810 mg, 5.0 mmol) was dissolved in 10 mL of N, N-dimethylacetamide in an ice bath, Sodium hydride (300 mg, 7.5 mmol) was added. The reaction solution was heated to room temperature and then stirred for 10 minutes. Tetrahydrofuran-3-ylmethanesulfonate 30b (1.66 g, 10.0 mmol, prepared according to the method disclosed in Journal of Organic Chemistry, 2008, 73 (14), 5397-5409) was added and the mixture was added at 50 ^° C. And stirred for 16 hours. 100 mL of water was added to the reaction mixture, stirred well, and then extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with a saturated solution of sodium chloride (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound 5-nitro-1-tetrahydrofuran-3-yl-1H-indole 30c (1.16 g) as a white solid. This was used in the next step without further purification.
MS m / z (ESI): 233.1 [M + 1]

Process 2
5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
After 5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 30c (1.16 g, 5.0 mmol) was dissolved in 10 mL of N, N-dimethylacetamide, 1-iodo-4- (trifluoromethyl ) Benzene 1i (1.36 g, 5.0 mmol), triphenylphosphine (282 mg, 1.0 mmol), palladium acetate (113 mg, 0.5 mmol) and cesium acetate (1.9 g, 10 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system C to give the title compound 5-nitro-1- (tetrahydrofuran-3-yl) -2- (4- (4- ( Trifluoromethyl) phenyl) -1H-indole 30d (200 mg, 10.6%) was obtained.
MS m / z (ESI): 377.1 [M + 1]

Process 3
5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
After 5-nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 30d (100 mg, 0.27 mmol) was dissolved in 10 mL of tetrahydrofuran, Raney nickel ( 10 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom and the filter cake was washed with ethyl acetate (30 mL). The filtrate was concentrated under reduced pressure to give the title compound 5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 30e (85 mg, 92.4%) as a yellow solid. )
MS m / z (ESI): 347.1 [M + 1]

Process 4
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) Phenyl) -1H-indol-5-yl) nicotinamide
5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 30e (70 mg, 0.20 mmol), 2- (difluoromethyl) -5-(( (2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (58 mg, 0.20 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg, 0.30 mmol), 1- Hydroxybenzotriazole (3 mg, 0.02 mmol) and N, N-diisopropylethylamine (52 mg, 0.40 mmol) were added sequentially to 10 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2- (difluoromethyl) -5-((((2 -Fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 30 (20 mg, 16.1%) was obtained.
MS m / z (ESI): 619.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.87 (s, 1H), 8.69 (t, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 8.01 -7.91 (m, 2H), 7.78-7.76 (m, 2H), 7.72-7.69 (m, 1H), 7.40-7.39 (m, 1H), 7.18 (t, 1H), 6.65 (s, 1H), 5.13 (m, 1H), 4.68-4.67 (m, 2H), 4.48-4.46 (m, 1H), 4.32-4.17 (m, 1H), 3.96-3.91 (m, 1H), 3.67-3.65 (m, 1H) , 2.40-2.33 (m, 2H), 1.54-1.42 (d, 6H).

(S) -2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- ( (Trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide

Process 1
(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -1H-indole
5-Nitroindole 30a (9.0 g, 55.3 mmol) and cesium carbonate (36.0 g, 110.6 mmol) were dissolved in 100 mL of N, N-dimethylacetamide, and (R) tetrahydrofuran-3-yl methanesulfonate 31a (18.4 g, 110.6 mmol, prepared according to the method disclosed in Nature Chemical Biology, 2008, 4 (11), 691-699). The reaction mixture was heated to 70 ^° C. and stirred for 16 hours. The reaction solution was poured into 400 mL of ice-water, and a large amount of solid precipitated, which was filtered. The filter cake was dissolved in ethyl acetate and filtered. The filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (S) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 31b (12 g, 93.8%) as a yellow solid.
MS m / z (ESI): 233.0 [M + 1]

Process 2
(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
After dissolving (S) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 31b (2.0 g, 8.6 mmol) in 15 mL of N, N-dimethylacetamide, 1-iodo-4- (Trifluoromethyl) benzene 1i (2.58 g, 9.5 mmol), triphenylphosphine (450 mg, 1.7 mmol), palladium acetate (97 mg, 0.4 mmol) and cesium acetate (5.0 g, 25.9 mmol) were added sequentially. . The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. 200 mL of water was added to the reaction solution, and extracted with ethyl acetate (200 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using elution system C to give the title compound (S) -5-nitro-1- (tetrahydrofuran-3-yl) -2- ( 4- (Trifluoromethyl) phenyl) -1H-indole 31c (200 mg, 5.3%) was obtained.
MS m / z (ESI): 377.1 [M + 1]

Process 3
(S) -5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
(S) -5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 31c (200 mg, 0.53 mmol) in 10 mL of tetrahydrofuran and methanol After dissolving in the mixture (V: V = 1: 1), Raney nickel (20 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through Ceratom and the filtrate was concentrated under reduced pressure to give a pale yellow solid, i.e., the title compound (S) -5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoro Methyl) phenyl) -1H-indole 31d (130 mg, 70.7%) was obtained.
MS m / z (ESI): 347.2 [M + 1]

Process 4
(S) -2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- ( (Trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide
(S) -5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 31d (130 mg, 0.38 mmol), 2- (difluoromethyl)- 5-(((2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (58 mg, 0.20 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg, 0.30 mmol ), 1-hydroxybenzotriazole (4 mg, 0.03 mmol) and triethylamine (139 mg, 1.38 mmol) were sequentially added to 5 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound (S) -2- (difluoromethyl) -5-(((2-fluoro- 2-Methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 31 (100 mg, 46.9%).
MS m / z (ESI): 619.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.63 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 8.12 (s, 1H), 8.01-8.12 (d, 1H) , 7.89-7.91 (d, 2H), 7.75-7.77 (d, 2H), 7.69-7.71 (d, 1H), 7.39-7.40 (d, 1H), 7.31 (t, 1H), 6.64 (s, 1H) , 4.46-4.48 (d, 2H), 4.32-4.35 (m, 1H), 4.13-4.17 (m, 1H), 3.91-3.95 (m, 1H), 3.65-3.67 (m, 1H), 2.42-2.45 ( m, 1H), 2.32-2.36 (m, 1H), 1.98-2.04 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H).

 (R) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- ( (Trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide

Process 1
(R) -5-Nitro-1- (tetrahydrofuran-3-yl) -1H-indole
5-Nitroindole 30a (5.0 g, 30.8 mmol) and cesium carbonate (20.0 g, 61.3 mmol) were dissolved in 70 mL of N, N-dimethylacetamide, and (S) -tetrahydrofuran-3-yl methanesulfonate 32a ( 10.0 g, 60.2 mmol, prepared according to the method disclosed in Nature Chemical Biology, 2008, 4 (11), 691-699). The reaction mixture was heated to 70 ^° C. and stirred for 16 hours. The reaction solution was poured into 400 mL of ice-water, and a large amount of solid precipitated, which was filtered. The filter cake was washed with water (50 mL × 3) and dried to give the title compound (R) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 32b (7.0 g) as a yellow solid. It was. This was used in the next step without further purification.
MS m / z (ESI): 233.0 [M + 1]

Process 2
(R) -5-Nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
(R) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 32b (2.0 g, 8.6 mmol) was dissolved in 80 mL of N, N-dimethylacetamide and 1-iodo-4- (Trifluoromethyl) benzene 1i (2.34 g, 8.6 mmol), triphenylphosphine (485 mg, 1.7 mmol), palladium acetate (200 mg, 0.86 mmol) and cesium acetate (2.5 g, 12.9 mmol) were added sequentially. . The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by TLC using elution system C to give the title compound (R) -5-nitro-1- (tetrahydrofuran-3-yl) -2- (4- (Trifluoromethyl) phenyl) -1H-indole 32c (300 mg, 9.4%) was obtained.
MS m / z (ESI): 377.3 [M + 1]

Process 3
(R) -5-Amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole
(R) -5-nitro-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 32c (200 mg, 0.53 mmol) was added to 10 mL of tetrahydrofuran and methanol. After dissolving in the mixture (V: V = 1: 1), Raney nickel (20 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through Ceratom and the filtrate was concentrated under reduced pressure to give the title compound (R) -5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) as a yellow solid. ) Phenyl) -1H-indole 32d (184 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 347.0 [M + 1]

Process 4
(R) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- ( (Trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide
(R) -5-amino-1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indole 32d (160 mg, 0.55 mmol), 2- (difluoromethyl)- 5-(((2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (190 mg, 0.55 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (158 mg, 0.83 mmol ), 1-hydroxybenzotriazole (7 mg, 0.05 mmol) and N, N-diisopropylethylamine (142 mg, 1.1 mmol) were sequentially added to 10 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by silica gel column chromatography using elution system A to give the title compound (R) -2- (difluoromethyl) -5-(((2- Fluoro-2-methyl-propanoyl) amino) methyl) -N- (1- (tetrahydrofuran-3-yl) -2- (4- (trifluoromethyl) phenyl) -1H-indol-5-yl) nicotinamide 32 (100 mg, 29.4%) was obtained.
MS m / z (ESI): 619.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 8.88 (s, 1H), 8.69 (t, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.91 -7.89 (m, 2H), 7.78-7.76 (m, 2H), 7.71-7.69 (m, 1H), 7.40-7.39 (m, 1H), 7.31 (t, 1H), 6.65 (s, 1H), 5.13 (m, 1H), 4.48-4.46 (m, 2H), 4.34-4.30 (m, 1H), 4.17-4.14 (m, 1H), 3.95-3.93 (m, 1H), 3.67-3.65 (m, 1H) , 2.45-2.33 (m, 2H), 1.53-1.48 (d, 6H).

N- (2- (3-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide

Process 1
2- (3-Chlorophenyl) -1-methyl-5-nitro-1H-indole
1-Methyl-5-nitro-1H-indole 9a (2.0 g, 11.4 mmol) was dissolved in 20 mL of N, N-dimethylacetamide and then 1-chloro-3-iodo-benzene 20a (2.7 g, 11.3 mmol ), Triphenylphosphine (620 mg, 2.2 mmol), palladium acetate (250 mg, 1.1 mmol) and cesium acetate (4.2 g, 22.0 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture is concentrated under reduced pressure and the residue is purified by TLC using elution system B to give a pale yellow solid, ie the title compound 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-indole 33a (300 mg, 9.5%) was obtained.
MS m / z (ESI): 287.1 [M + 1]

Process 2
2- (3-Chlorophenyl) -1-methyl-1H-indole-5-amine
After 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-indole 33a (300 mg, 1.05 mmol) was dissolved in 20 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel (30 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to obtain a crude product (269 mg) of the title compound 2- (3-chlorophenyl) -1-methyl-1H-indole-5-amine 33b as a yellow solid. This was used in the next step without further purification.
MS m / z (ESI): 257.1 [M + 1]

Process 3
N- (2- (3-chlorophenyl) -1-methyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) Nicotinamide
2- (3-Chlorophenyl) -1-methyl-1H-indole-5-amine 33b (269 mg, 1.05 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) Amino) methyl) nicotinic acid 14b (305 mg, 1.05 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (302 mg, 1.58 mmol), 1-hydroxybenzotriazole (14 mg, 0.10 mmol) and N, N-diisopropylethylamine (271 mg, 2.1 mmol) was added sequentially to 10 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by silica gel column chromatography using elution system A to give the title compound N- (2- (3-chlorophenyl) -1-methyl-1H-indole as a white solid. -5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 33 (30 mg, 5.4% over 2 steps) was obtained.
MS m / z (ESI): 529.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H), 8.06 (d, 2H), 7.69 (s, 1H), 7.56 -7.51 (m, 4H), 7.45-7.44 (m, 1H), 7.20 (s, 1H), 6.69 (s, 1H), 4.48-4.46 (m, 2H), 3.77 (s, 3H), 1.54 (s , 3H), 1.48 (s, 3H)

2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzamide

Process 1
2-Chloro-5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic acid
5- (Aminomethyl) -2-chlorobenzoic acid 34a (1.5 g, 6.8 mmol, prepared according to the method disclosed in the patent application “WO2011048004”) and N, N-diisopropylethylamine (2.63 g, 20.3 mmol) Was dissolved in 4 mL of dichloromethane and cooled to 0 ^° C. in an ice bath. 1- (Trifluoromethyl) cyclopropanecarbonyl chloride 34b (1.28 g, 7.5 mmol, prepared according to the method disclosed in patent application “WO2005023773”) was added and the reaction mixture was heated to room temperature and stirred for 5 hours . The reaction mixture was concentrated under reduced pressure to give a pale yellow oil, i.e. crude product of the title compound 2-chloro-5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic acid 34c (2.4 g) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 320.1 [M-1]

Process 2
2-Chloro-5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl chloride
2-Chloro-5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoic acid 34c (200 mg, 0.62 mmol) and thionyl chloride (222 mg, 1.86 mmol) in 20 mL dichloromethane After dissolution, 1 drop of N, N-dimethylformamide was added. The reaction mixture was stirred for 3 hours. The reaction mixture is then concentrated under reduced pressure to give a pale yellow oil, ie crude product of the title compound 2-chloro-5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl chloride 34d. (210 mg) was obtained. This was used in the next step without further purification.

Process 3
2-Chloro-N- (2- (4-fluorophenyl) -1-methyl-1H-indol-5-yl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzamide
2- (4-Fluorophenyl) -1-methyl-5-amino-1H-indole 11b (85 mg, 0.35 mmol) was dissolved in 10 mL of dichloromethane and then 2-chloro-5-(((1- ( Trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzoyl chloride 34d (120 mg, 0.35 mmol) and N, N-diisopropylethylamine (90 mg, 0.70 mmol) were added. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2-chloro-N- (2- (4- (4- Fluorophenyl) -1-methyl-1H-indol-5-yl) -5-(((1- (trifluoromethyl) cyclopropanecarbonyl) amino) methyl) benzamide 34 (20 mg, 10.5%) was obtained.
MS m / z (ESI): 544.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (s, 1H), 8.47 (s, 1H), 8.06 (s, 1H), 7.66-7.64 (m, 2H), 7.53-7.35 (m, 7H), 6.58 (s, 1H), 4.34-4.32 (m, 2H), 3.73 (s, 3H), 1.34-1.24 (m, 4H).

N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
6-Chloro-2-iodo-pyridin-3-amine
After dissolving 6-chloropyridin-3-amine 35a (1 g, 7.78 mmol) in 20 mL of N, N-dimethylformamide, N-iodosuccinimide (2.27 g, 10.11 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 6-chloro-2-iodo-pyridin-3-amine 35b (1.37 g, 69.2%) as a brown solid.

Process 2
6-Chloro-2- (2- (3-chlorophenyl) ethynyl) pyridin-3-amine
6-chloro-2-iodo-pyridin-3-amine 35b (1.37 g, 5.38 mmol), 3-chlorophenylacetylene (882 mg, 6.46 mmol), bis (triphenylphosphine) palladium (II) chloride (378 mg, 0.54 mmol), cuprous iodide (205 mg, 1.08 mmol) and N, N-diisopropylethylamine (1.39 g, 10.76 mmol) were added to 10 mL of N, N-dimethylformamide. The reaction mixture was stirred at 100 ^° C. for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 6-chloro-2-((3-chlorophenyl) ethynyl) pyridin-3-amine 35c (871 mg, 61.6%) as a brown solid )

Process 3
5-Chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-b] pyridine
6-Chloro-2-((3-chlorophenyl) ethynyl) pyridin-3-amine 35c (871 mg, 3.32 mmol) and potassium tert-butanolate (746 mg, 6.64 mmol) into 20 mL of N, N-dimethylformamide Dissolved. The resulting mixture was stirred at 70 ^° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and 10 mL of ethyl acetate was added to the residue and filtered. The filtrate was concentrated under reduced pressure to give a crude product (1.17 g) of the title compound 5-chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-b] pyridine 35d as a yellow solid. This was used in the next step without further purification.

Process 4
5-Chloro-2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridine
5-Chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-b] pyridine 35d (1.17 g, 4.46 mmol) was dissolved in 15 mL of N, N-dimethylformamide and then 60% hydrogenated. Sodium (268 mg, 6.69 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Iodomethane (761 mg, 5.36 mmol) was added and stirred continuously at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system C to give the title compound 5-chloro-2- (3-chlorophenyl) -1-methyl-1H as a yellow solid. -Pyrrolo [3,2-b] pyridine 35e (650 mg, 52.8%) was obtained.

Process 5
2- (3-Chlorophenyl) -N- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-amine
5-chloro-2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridine 35e (276 mg, 1.0 mmol), 4-methoxybenzylamine (172 mg, 1.25 mmol), tris (Dibenzylideneacetone) dipalladium (92 mg, 0.1 mmol), (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (125 mg, 0.2 mmol) and potassium phosphate (425 mg, 2 mmol) was dissolved in 15 mL of 1,4-dioxane. The reaction mixture was stirred at 100 ^° C. for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (3-chlorophenyl) -N- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3 , 2-b] pyridin-5-amine 35f (221 mg, 58.5%) was obtained.

Step 6
N- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2,2,2-trifluoro-acetamide
2- (3-Chlorophenyl) -N- (4-methoxybenzyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-amine 35f (221 mg, 0.58 mmol) in 5 mL of trifluoro Dissolved in acetic acid. The resulting mixture was stirred at 60 ^° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a brown oil, ie the title compound N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2 2,2-Trifluoroacetamide 35h crude product (207 mg) was obtained. This was used in the next step without further purification.

Step 7
2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-amine
N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2,2,2-trifluoroacetamide 35h (207 mg, 0.58 mmol) and Potassium carbonate (162 mg, 1.17 mmol) was dissolved in 10 mL of ethanol. The reaction mixture was stirred at 80 ^° C. for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2- (3-chlorophenyl) -1-methyl-1H- Pyrrolo [3,2-b] pyridin-5-amine 35j (30 mg, 20%) was obtained.

Process 8
N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (34 mg, 0.12 mmol) and 2- (3-chlorophenyl) -1-methyl-1H -Pyrrolo [3,2-b] pyridin-5-amine 35j (30 mg, 0.12 mmol) was dissolved in 15 mL of N, N-dimethylformamide, then triethylamine (47 mg, 0.46 mmol), 1-hydroxybenzo Triazole (16 mg, 0.12 mmol) and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (34 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a slightly off-white solid, ie the title compound N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 35 (3 mg, 4.8%) was obtained.
MS m / z (ESI): 530.1 [M + 1]
¹ H NMR (400MHz, CDCl ₃ ): δ 8.63 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.54-7.43 (m, 4H), 7.31 ( s, 1H), 6.93 (s, 1H), 6.42 (s, 1H), 4.43 (s, 2H), 3.83 (s, 3H), 1.64 (s, 3H), 1.59 (s, 3H).

N- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
4-Iodo-6-nitro-pyridin-3-amine
5-amino-2-nitropyridine 36a (1 g, 7.2 mmol), potassium iodate (770 mg, 3.6 mmol) and potassium iodide (1.2 g, 7.2 mmol) were added sequentially to 30 mL of sulfuric acid (2N). It was. The reaction solution was stirred at 80 ^° C. for 16 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to 10 with 2N aqueous sodium hydroxide solution. A large amount of solid precipitated and was filtered. The filter cake was washed with water and dried to give the title compound 4-iodo-6-nitro-pyridin-3-amine 36b (1.5 g, 79%) as a yellow solid.

Process 2
4-((3-Chlorophenyl) ethynyl) -6-nitro-pyridin-3-amine
4-Iodo-6-nitro-pyridin-3-amine 36b (1.5 g, 5.7 mmol), 3-chlorophenylacetylene (850 mg, 6.2 mmol), cuprous iodide (1.1 g, 5.7 mmol), (1, 1′-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (834 mg, 1.14 mmol) and triethylamine (1.6 mL, 11.4 mmol) were added sequentially to 20 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 h under an argon atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system A to give the title compound 4-((3-chlorophenyl) ethynyl) -6-nitro-pyridin-3-amine 36c (1.5 g, 97%) as a yellow solid. Obtained.

Process 3
2- (3-Chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine
In a 50 mL flask was 4-((3-chlorophenyl) ethynyl) -6-nitro-pyridin-3-amine 36c (200 mg, 0.73 mmol), potassium tert-butanolate (123 mg, 1.1 mmol) and 10 mL of N. N-dimethylformamide was added. The resulting mixture was stirred at 60 ^° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a brown oil, ie the crude product (300 mg) of the title compound 2- (3-chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine 36d. It was. This was used in the next step without further purification.

Process 4
2- (3-Chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-c] pyridine
In a 100 mL flask was 2- (3-chlorophenyl) -5-nitro-1H-pyrrolo [2,3-c] pyridine 36d (300 mg, 1.1 mmol), iodomethane (233 mg, 1.64 mmol), cesium carbonate (717 mg, 2.2 mmol) and 10 mL of N, N-dimethylformamide. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-c] as a yellow solid Pyridine 36e (50 mg, 15.8%) was obtained.

Process 5
2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-amine
In a 50 mL flask was 2- (3-chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-c] pyridine 36e (50 mg, 0.17 mmol), Raney nickel (5 mg) and 10 mL. Tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid, ie the title compound 2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-amine 36f (40 mg, 88.9% )

Step 6
N- (2- (3-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-c] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (45 mg, 0.16 mmol), 2- (3-chlorophenyl) -1-methyl-1H -Pyrrolo [2,3-c] pyridin-5-amine 36f (40 mg, 0.16 mmol), 1-hydroxybenzotriazole (2.2 mg, 0.016 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride (46 mg, 0.24 mmol) and N, N-diisopropylethylamine (31 mg, 0.24 mmol) were dissolved in N, N-dimethylformamide. The reaction mixture was stirred at 70 ^° C. for 2 hours and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to obtain a pale yellow solid, ie the title compound N- (2- (3-chlorophenyl) -1-methyl-1H-pyrrolo [2,3- c] Pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 36 (20 mg, 23.5%) was obtained.
MS m / z (ESI): 530.1 [(M + 1])
¹ H NMR (400MHz, DMSO-d ₆ ): δ 11.15 (s, 1H), 8.82-8.80 (m, 1H), 8.67 (s, 1H), 8.07-8.05 (m, 3H), 7.75 (s, 1H ), 7.66-7.65 (m, 1H), 7.57-7.55 (m, 2H), 7.21 (s, 1H), 6.72 (s, 1H), 4.46-4.44 (d, 2H), 3.83 (s, 3H), 1.53 (s, 3H), 1.48 (s, 3H).

N- (2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinoyl chloride
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (1.5 g, 5.17 mmol) was dissolved in 10 mL of dichloromethane and then thionyl chloride (1.2 mL, 15.5 mmol) and 2 drops of N, N-dimethylformamide were added. The reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give the title compound 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinoyl as a white solid. A crude product of chloride 37a (1.6 g) was obtained. This was used in the next step without further purification.

Process 2
5-Chloro-2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridine
5-Chloro-2- (3-chlorophenyl) -1H-pyrrolo [3,2-b] pyridine 35d (0.87 g, 3.32 mmol) was dissolved in 20 mL of N, N-dimethylformamide and then 60% hydrogenated. Sodium (0.2 g, 4.98 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, iodomethane (0.62 g, 3.98 mmol) was added, and the mixture was further stirred at room temperature for 2 hr. 10 mL of water was added to the reaction mixture and concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to give a yellow oil, ie the title compound 5-chloro-2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2 -b] pyridine 37b (0.35 g, 36.3%) was obtained.

Process 3
(2- (3-Chlorophenyl) -N- (diphenylmethylene) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-amine
5-chloro-2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridine 37b (30 mg, 0.1 mmol), benzophenone imine (22 mg, 0.12 mmol), tris (dibenzylidene) Acetone) dipalladium (9.5 mg, 0.01 mmol), 4,5-bis (diphenylphosphino) -9.9-dimethylxanthene (12 mg, 0.021 mmol) and potassium phosphate (44 mg, 0.21 mmol) It was dissolved in 4-dioxane. The resulting mixture was stirred at 100 ^° C. for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. A small amount of tetrahydrofuran was added to the residue and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2- (3-chlorophenyl) -N- (diphenylmethylene) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-amine 37c as a gray solid. A crude product (50 mg) was obtained, which was used in the next step without further purification.

Process 4
2- (3-Chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-amine
(2- (3-Chlorophenyl) -N- (diphenylmethylene) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-amine 37c (50 mg, 0.12 mmol) dissolved in 10 mL of tetrahydrofuran After that, 4 mL of 2M hydrochloric acid solution was added and the reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, then adjusted to pH> 7 with saturated sodium bicarbonate solution. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b ] Crude product (62 mg) of pyridine-5-amine 37d was obtained and used in the next step without further purification.

Process 5
N- (2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinoyl chloride 37a (13.5 mg, 0.044 mmol) was dissolved in 10 mL of dichloromethane and triethylamine (94 mg, 0.088 mmol) and 2- (3-chlorophenyl) -1-ethyl-1H-pyrrolo [3,2-b] pyridin-5-amine 37d (11.9 mg, 0.044 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure, and the residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound N- (2- (3-chlorophenyl) as a white solid. ) -1-Ethyl-1H-pyrrolo [3,2-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotine Amide 37 (5 mg, 20.8%) was obtained.
MS m / z (ESI): 544.1 [M + 1]
¹ H NMR (400MHz, CDCl ₃ ): δ 13.16 (s, 1H), 8.84-8.82 (d, 2H), 8.72-8.70 (d, 1H), 8.26-8.24 (d, 1H), 7.57-7.52 (m , 3H), 7.43-7.42 (d, 1H), 7.36-7.31 (m, 2H), 6.81 (s, 1H), 4.71-4.69 (d, 2H), 4.39-4.33 (m, 2H), 1.64 (s , 3H), 1.59 (s, 3H), 1.44-1.42 (m, 3H).

2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide
2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (120 mg, 0.44 mmol) was dissolved in 5 mL of N, N-dimethylformamide and then 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (100 mg, 0.37 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (140 mg, 0.74 mmol), 1 -Hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (200 μL, 1.47 μmol) were added. The resulting mixture was heated to 70 ^° C. and stirred for 3 hours. The reaction solution was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) as a white solid. -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 38 (60 mg, 30.6%) was obtained.
MS m / z (ESI): 533.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.00 (s, 1H), 8.81 (s, 1H), 8.61 (t, 1H), 8.21-8.27 (m, 3H), 8.10 (s, 1H) , 7.83 (d, 1H), 7.72 (d, 3H), 7.22 (t, 1H), 4.44 (d, 2H), 2.49 (d, 1H), 1.06 (d, 6H).

2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide
5-Amino-2- (4- (trifluoromethyl) phenyl) benzofuran 29d (70 mg, 0.25 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f ( 69 mg, 0.25 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol), 1-hydroxybenzotriazole (3 mg, 0.025 mmol) and triethylamine (140 μL, 0.80 μmol) was sequentially added to 5 mL of N, N-dimethylformamide. The resulting mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a slightly off-white solid, ie the title compound 2- (difluoromethyl) -5- ( (2-Methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide 39 (70 mg, 52.2%) was obtained.
MS m / z (ESI): 532.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.81 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 8.15 (d, 2H), 8.04 (s, 1H), 7.89 (d, 2H), 7.73 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 4.44 (d, 2H), 2.47 ( d, 1H), 1.06 (d, 6H).

2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotinamide
2- (4- (Trifluoromethyl) phenyl) isoindoline-5-amine 25d (10 mg, 0.036 mmol) and 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (10 mg, 0.036 mmol) was dissolved in 5 mL of N, N-dimethylformamide, then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (11 mg, 0.054 mmol) and 1-hydroxybenzo Triazole (5 mg, 0.036 mmol) was added. The resulting mixture was stirred for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -5-((2-methylpropanoylamino) as a white solid. ) Methyl) -N- (2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotinamide 40 (10 mg, 52.6%) was obtained.
MS m / z (ESI): 533.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.66 (s, 1H), 8.44 (d, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.88 -7.85 (m, 4H), 7.54 (d, 1H), 7.47 (d, 1H), 7.42 (t, 1H), 4.60 (s, 4H), 4.41 (d, 2H), 3.18-3.17 (m, 1H ), 1.05 (s, 6H)

2-Chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide

Process 1
2-Chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoic acid
5- (aminomethyl) -2-chloro-benzoic acid 34a (1.5 g, 6.8 mmol, prepared according to the method disclosed in patent application “WO2011048004”) and triethylamine (3.2 mL, 23.2 mmol) in 15 mL After dissolving in tetrahydrofuran, it was cooled to 0 ^° C. in an ice bath. 5 mL of 1-methylcyclopropanecarbonyl chloride 41a (890 mg, 7.47 mmol, prepared according to the method disclosed in Journal of Medicinal Chemistry, 2014, 57 (22), 9323-9342) in tetrahydrofuran Added dropwise to the mixture. The reaction mixture was heated to room temperature and then stirred for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the crude product (4.78 g,) of the title compound 2-chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoic acid 41b as a white solid. . This was used in the next step without further purification.
MS m / z (ESI): 266.1 [M-1]

Process 2
2-Chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoyl chloride
2-Chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoic acid 41b (200 mg, 0.75 mmol) was dissolved in 10 mL of dichloromethane, and thionyl chloride (0.2 mL, 2.75 mmol) was added. added. The reaction solution was stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow oil, crude product of the title compound 2-chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoyl chloride (220 mg). This was used in the next step without further purification.

Process 3
2-Chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide
2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (90 mg, 0.33 mmol) and triethylamine (90 μL, 0.65 μmol) were dissolved in 5 mL of tetrahydrofuran, and then 5 mL. Of 2-chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) benzoyl chloride 41c (220 mg, 0.72 mmol) was added dropwise. The reaction mixture was stirred for 30 minutes. The reaction mixture was then filtered and concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2-chloro-5-(((1-methylcyclopropanecarbonyl) amino) methyl) -N- (2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) benzamide 41 (30 mg, 17.4% over 2 steps) was obtained.
MS m / z (ESI): 528.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.78 (s, 1H), 8.42 (d, 2H), 8.33 (s, 1H), 8.23 (t, 1H), 8.01 (d, 2H), 7.84 (d, 1H), 7.72 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.39 (d, 1H), 4.31 (d, 2H), 1.30 (s, 3H), 0.97 ( d, 2H), 0.54 (d, 2H).

N- (2- (4-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide

Process 1
Ethyl 2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinate Ethyl 5- (aminomethyl) -2- (difluoromethyl) nicotinic acid hydrochloride 1d (1.8 g, 5.94 mmol ) In 25 mL of N, N-dimethylformamide, 1-methylcyclopropane-1-carboxylic acid 42a (594 mg, 5.94 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Salt (2.28 g, 11.9 mmol), 1-hydroxybenzotriazole (80 mg, 0.59 mmol) and triethylamine (3.3 mL, 23.8 mmol) were added sequentially. The resulting mixture was stirred for 16 hours and concentrated under reduced pressure. 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (25 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using elution system C to give a pale yellow oil, ie the title compound ethyl 2- (difluoromethyl) -5-((((1-methylcyclohexane Propanecarbonyl) -amino) methyl) nicotinate 42b (1.2 g, 64.9%) was obtained.
MS m / z (ESI): 313.2 (M + 1)

Process 2
2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) ethyl nicotinate 2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) -amino) methyl) Nicotinate 42b (1.2 g, 3.85 mmol) was dissolved in 30 mL of a mixture of 1,4-dioxane and water (V: V = 2: 1), and then lithium hydroxide hydrate (400 mg, 9.62 mmol) was added. added. The reaction mixture was stirred for 16 hours. 1,4-Dioxane was removed under reduced pressure, and the pH of the residue was adjusted to 4-5 with 6M hydrochloric acid. A large amount of solid precipitated and 30 mL of ethyl acetate was added to it and filtered. The filter cake was collected and the filtrate was separated. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was combined with the above filter cake and the title compound 2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinic acid 42c (1.0 g, 91.7%).
MS m / z (ESI): 285.1 [M + 1].

Process 3
N- (2- (4-Chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide
2- (Difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinic acid 42c (52 mg, 0.19 mmol), 1-ethyl-2- (4-chlorophenyl) -5-amino- 1H-indole 10c (50 mg, 0.19 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (71 mg, 0.37 mmol), 1-hydroxybenzotriazole (2.5 mg, 18.5 μmol) and triethylamine (100 μL, 0.74 mmol) was dissolved in 5 mL of N, N-dimethylformamide. The reaction mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to afford the title compound N- (2- (4-chlorophenyl) -1-ethyl-1H-indol-5-yl) -2- (Difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) nicotinamide 42 (40 mg, 40.4%) was obtained.
MS m / z (ESI): 538.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 8.04 (d, 2H), 7.55-7.69 (m, 3H) , 7.44 (d, 2H), 7.19 (t, 1H), 6.60 (s, 1H), 4.43 (d, 2H), 4.22 (d, 2H), 1.32 (s, 3H), 1.20 (t, 3H), 1.00 (s, 3H), 0.56 (s, 2H).

2- (Difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotine Amide
2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 22c (50 mg, 0.18 mmol) was dissolved in 5 mL of N, N-dimethylformamide and then 2- (difluoromethyl) -5-(((1-Methylcyclopropanecarbonyl) amino) methyl) nicotinic acid 42c (51 mg, 0.18 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75 mg, 0.39 mmol ), 1-hydroxybenzotriazole (2.4 mg, 0.018 mmol) and triethylamine (0.1 mL, 720 μmol) were added. The reaction mixture was heated to 70 ^° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound 2- (difluoromethyl) -5-(((1-methylcyclopropanecarbonyl) amino) methyl) -N- (2- (4- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 43 (20 mg, 20.4%) was obtained.
MS m / z (ESI): 545.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.95 (s, 1H), 8.70 (d, 1H), 8.43 (d, 2H), 8.30 (t, 2H), 8.03 (d, 3H), 7.87 (d, 1H), 7.72 (d, 1H), 7.19 (t, 1H), 4.43 (d, 2H), 1.31 (s, 3H), 0.99 (d, 2H), 0.56 (d, 2H).

N- (2- (4-Chlorophenyl) -1-methyl-1H-pyrrolo (2,3-b) pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2- Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
3-((4-Chlorophenyl) ethynyl) -5-nitro-pyridin-2-amine
2-Amino-3-iodo-5-nitro-pyridine 44b (300 mg, 1.13 mmol), 4-chlorophenylacetylene 44a (325 mg, 2.38 mmol), bis (triphenylphosphine) palladium (II) chloride (40 mg, 56.5 μmol), cuprous iodide (11 mg, 56.5 μmol) and triethylamine (1.6 mL, 11.3 mmol) were sequentially added to 20 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours under an argon atmosphere. 100 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed with water (50 mL × 2). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A to afford the title compound 3-((4-chlorophenyl) ethynyl) -5-nitro-pyridin-2-amine 44c (250 mg, 80.9 %).
MS m / z (ESI): 272.0 [M-1]

Process 2
2- (4-Chlorophenyl) -5-nitro-1H-pyrrolo (2,3-b) pyridine
3-((4-Chlorophenyl) ethynyl) -5-nitro-pyridin-2-amine 44c (160 mg, 0.58 mmol) and potassium tert-butanolate (746 mg, 6.64 mmol) in 10 mL of N, N-dimethylformamide Dissolved in. The reaction mixture was heated to 70 ^° C. and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was mixed with 50 mL ethyl acetate and filtered. The filtrate was concentrated under reduced pressure to give a crude product (160 mg) of the title compound 2- (4-chlorophenyl) -5-nitro-1H-pyrrolo (2,3-b) pyridine 44d as a yellow solid. This was used in the next step without further purification.
MS m / z (ESI): 273.0 [M-1]

Process 3
2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-b] pyridine
2- (4-Chlorophenyl) -5-nitro-1H-pyrrolo [2,3-b] pyridine 44d (160 mg, 0.58 mmol) was dissolved in 5 mL of N, N-dimethylformamide, and then cesium carbonate (380 mg, 1.17 mmol) and iodomethane (73 μL, 1.17 mmol) were added. The reaction mixture was stirred for 3 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system C to give the title compound 2- (4-chlorophenyl) -1-methyl-5-nitro as a yellow solid. -1H-pyrrolo [2,3-b] pyridine 44e (30 mg, 17.9% over 2 steps) was obtained.
MS m / z (ESI): 290.0 [M + 1]

Process 4
2- (4-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b] pyridinyl-5-amine
2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-pyrrolo [2,3-b] pyridine 44e (50 mg, 0.17 mmol) was mixed with 10 mL of tetrahydrofuran and methanol (V: V = 1 1) and then Raney nickel (30 mg) was added. The reaction mixture was stirred for 1 hour under hydrogen atmosphere. The reaction mixture is then filtered through Ceratom and the filtrate is concentrated under reduced pressure to give a pale yellow solid, ie the title compound 2- (4-chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b] pyridinyl- A crude product (45 mg) of 5-amine 44f was obtained. This was used in the next step without further purification.
MS m / z (ESI): 259.1 [M + 1]

Process 5
N- (2- (4-Chlorophenyl) -1-methyl-1H-pyrrolo [(2,3-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2 -Methyl-propanoyl) amino) methyl) nicotinamide
2- (4-Chlorophenyl) -1-methyl-1H-pyrrolo [2,3-b] pyridin-5-amine 44f (50 mg, 0.17 mmol), 2- (difluoromethyl) -5-(((2- Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (50 mg, 0.17 mmol), 1-ethyl- (3-dimethylaminopropyl) -3carbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxy Benzotriazole (2.3 mg, 17.4 μmol) was added sequentially to 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound N- (2- (4-chlorophenyl) -1-methyl-1H- Pyrrolo [2,3-b] pyridin-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 44 (3 mg, 3.3% )
MS m / z (ESI): 531.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.86 (s, 1H), 8.71 (s, 1H), 8.51 (t, 1H), 8.20-8.27 (m, 2H), 8.05 (s, 2H) , 7.82 (d, 1H), 7.71 (d, 2H), 7.19 (t, 1H), 6.55 (s, 1H), 4.47 (d, 2H), 3.83 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H).

N- (2- (4-Chlorophenyl) benzo [d] oxazol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
2- (4-Chlorophenyl) benzo [d] oxazol-5-amine
2,4-Diaminophenol (800 mg, 6.45 mmol) and 4-chlorobenzoic acid (1.1 g, 7.1 mmol) were dissolved in 10 ml of polyphosphoric acid. The reaction mixture was heated to 95 ^° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, poured into 50 mL of ice-water and sodium hydroxide solution was added dropwise to adjust the pH to 7. This mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (4-chlorophenyl) benzo [d] oxazol-5-amine 45a ( 90 mg, 5.7%).
MS m / z (ESI): 259.1 [M + 1]

Process 2
N- (2- (4-Chlorophenyl) benzo [d] oxazol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide
2- (4-Chlorophenyl) benzo [d] oxazol-5-amine 45a (80 mg, 0.33 mmol) and 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinic acid 1f (81 mg, 0.30 mmol) dissolved in 5 mL of N, N-dimethylformamide, then 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (67 mg, 0.35 mmol), 1-hydroxybenzotriazole (4 mg, 0.030 mmol) and triethylamine (0.16 mL, 1.19 μmol) were added. The reaction mixture was heated to 70 ^° C. and stirred for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system A and the title compound N- (2- (4-chlorophenyl) benzo [d] oxazol-5-yl) -2- (difluoromethyl) as a brown solid -5-((2-Methylpropanoylamino) methyl) nicotinamide 45 (6 mg, 4.1%) was obtained.
MS m / z (ESI): 499.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.96 (s, 1H), 8.70 (s, 1H), 8.51 (t, 1H), 8.20-8.27 (m, 3H), 8.05 (s, 1H) , 7.82 (d, 1H), 7.71 (d, 3H), 7.20 (t, 1H), 4.44 (d, 2H), 2.49 (d, 1H), 1.06 (d, 6H).

(S) -N- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro- 2-Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
(S) -2- (4-Chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole
(S) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 31b (2.0 g, 8.6 mmol) was dissolved in 15 mL of N, N-dimethylacetamide and then 4-chloroiodobenzene 46a. (2.3 g, 9.5 mmol), triphenylphosphine (450 mg, 1.7 mmol), palladium acetate (97 mg, 0.4 mmol) and cesium acetate (4.1 g, 21.6 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, 200 mL of water was added, and the mixture was extracted with ethyl acetate (200 mL × 1). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid (S) -2- (4-chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 46b (100 mg, 3.4%) Got.
MS m / z (ESI): 343.1 [M + 1]

Process 2
(S) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indole-5-amine
(S) -2- (4-Chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 46b (70 mg, 0.20 mmol) was mixed with 10 mL of tetrahydrofuran and methanol (V: V = 1)) and then Raney nickel (20 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give the title compound (S) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indole-5-amine 46c as a yellow solid (64 mg) Got. This was used in the next step without further purification.
MS m / z (ESI): 313.1 [M + 1]

Process 3
(S) -N- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro- 2-Methyl-propanoyl) amino) methyl) nicotinamide
(S) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indole-5-amine 46c (64 mg, 0.21 mmol), 2- (difluoromethyl) -5-((( 2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (100 mg, 0.35 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (63 mg, 0.69 mmol), 1-hydroxy Benzotriazole (4.7 mg, 0.03 mmol) and triethylamine (0.2 mL, 1.38 mmol) were added sequentially to 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound (S) -N- (2- (4-chlorophenyl)- 1- (Tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 46 (30 mg, 14.9%).
MS m / z (ESI): 586.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.86 (br, 1H), 8.69 (d, 1H), 8.09 (d, 1H), 8.01 (s, 1H), 7.67 (d, 2H), 7.61 (d, 2H), 7.55 (d, 1H), 7.36 (d, 1H), 7.18 (t, 1H), 6.55 (s, 1H), 5.11 (br, 1H), 4.47 ( d, 2H), 4.32 (t, 1H), 4.13 (dd, 1H), 3.91 (t, 1H), 3.66 (d, 1H), 2.36-2.45 (m, 1H), 2.26-2.32 (m, 1H) , 1.54 (s, 3H), 1.48 (s, 3H).

(R) -N- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro- 2-Methyl-propanoyl) amino) methyl) nicotinamide

Process 1
(R) -2- (4-Chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole
(R) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 32b (2.0 g, 8.6 mmol) was dissolved in 30 mL of N, N-dimethylacetamide and then 4-chloroiodo-benzene 46a (2.1 g, 8.6 mmol), triphenylphosphine (508 mg, 1.8 mmol), palladium acetate (200 mg, 0.86 mmol) and cesium acetate (3.5 g, 18 mmol) were sequentially added. The reaction mixture was heated to 140 ° C. and stirred for 18 hours under an argon atmosphere. The reaction mixture is then concentrated under reduced pressure and the residue purified by thin layer chromatography (TLC) using elution system B to give the title compound (R) -2- (4-chlorophenyl) -5-nitro as a yellow solid. -1- (Tetrahydrofuran-3-yl) -1H-indole 47a (280 mg, 9.0%) was obtained.
MS m / z (ESI): 343.9 [M + 1]

Process 2
(R) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indole-5-amine
(R) -2- (4-Chlorophenyl) -5-nitro-1- (tetrahydrofuran-3-yl) -1H-indole 47a (280 mg, 0.82 mmol) was dissolved in 20 mL of THF, and Raney nickel (28 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a crude product (230 mg) of the title compound (R) -2- (4-chlorophenyl) -1- (tetrahydrofuran-3-yl) -1Hindole-5-amine 47b as a yellow solid. Obtained. This was used in the next step without further purification.
MS m / z (ESI): 313.1 [M + 1]

Process 3
(R) -N- (2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro- 2-Methyl-propanoyl) amino) methyl) nicotinamide
(R) -2- (4-Chlorophenyl) -1- (tetrahydrofuran-3-yl) -1H-indole-5-amine 47b (230 mg, 0.74 mmol), 2- (difluoromethyl) -5-((( 2-Fluoro-2-methyl-propanoyl) amino) methyl) nicotinic acid 14b (213 mg, 0.74 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (211 mg, 1.1 mmol), 1-hydroxy Benzotriazole (10 mg, 0.074 mmol) and N, N-diisopropylethylamine (200 mg, 1.47 mmol) were added sequentially to 5 mL of N, N-dimethylformamide. The reaction mixture was stirred for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound (R) -N- (2- (4-chlorophenyl)- 1- (Tetrahydrofuran-3-yl) -1H-indol-5-yl) -2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) nicotinamide 47 (100 mg, 23.3%).
MS m / z (ESI): 586.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.61 (s, 1H), 8.86 (t, 1H), 8.68 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.76 (d, 1H), 7.61 (d, 2H), 7.55 (d, 2H), 7.38 (d, 1H), 7.18 (t, 1H), 6.55 (s, 1H), 5.10 (br, 1H), 4.47 ( d, 2H), 4.31 (t, 1H), 4.13 (d, 1H), 3.92 (t, 1H), 3.65 (dd, 1H), 2.40 (d, 1H), 2.32 (d, 1H), 1.54 (s , 3H), 1.48 (s, 3H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide

Process 1
5-Nitro-2- (3- (trifluoromethyl) phenyl) benzofuran
3- (Trifluoromethyl) (pinacorboryl) benzene 48a (143 mg, 0.53 mmol) and 2-bromo-5-nitro-benzofuran 48b (85 mg, 0.35 mmol, Organic & Biomolecular Chemistry, 2013, 11 (24), 4095 -4101) was dissolved in 6 mL of a mixture of 1,4-dioxane and water (V: V = 5: 1) and then (1,1′-bis (diphenylphosphine). Fino) ferrocene) -dichloropalladium (II) (26 mg, 0.036 mmol) and sodium carbonate (75 mg, 0.71 mmol) were added. The reaction mixture was heated to 100 ° C. and stirred for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (TLC) using elution system C to give the title compound 5-nitro-2- (3- (trifluoromethyl) phenyl) benzofuran 48c (64 mg, 64.0%) as a yellow solid. Obtained.

Process 2
2- (3- (Trifluoromethyl) phenyl) benzofuran-5-amine
After 5-nitro-2- (3- (trifluoromethyl) phenyl) benzofuran 48c (64 mg, 0.21 mmol) was dissolved in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1), Raney nickel ( 20 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a yellow oil, ie the title compound 2- (3- (trifluoromethyl) phenyl) benzofuran-5-amine 48d (45 mg, 77.6%).

Process 3
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide
2- (3- (trifluoromethyl) phenyl) benzofuran-5-amine 48d (23 mg, 0.083 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) Methyl) nicotinic acid 14b (24 mg, 0.083 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (32 mg, 0.17 mmol) and 1-hydroxybenzotriazole (11.2 mg, 0.083 mmol) Sequentially added to mL of N, N-dimethylacetamide. The reaction mixture was heated to 40 ^° C. and stirred for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2- (difluoromethyl) -5-(((2- Fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzofuran-5-yl) nicotinamide 48 (10 mg, 21.7%) was obtained.
MS m / z (ESI): 550.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.68 (s, 1H), 8.15-8.11 (d, 2H), 8.04-8.00 (d, 3H), 7.61-7.52 (m, 3H), 7.39- 7.38 (d, 1H), 7.15-6.85 (m, 3H), 4.58-4.57 (d, 2H), 1.64 (s, 3H), 1.58 (s, 3H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotine Amide

Process 1
6-Nitro-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one
3- (Trifluoromethyl) aniline 49a (773 mg, 4.8 mmol) was dissolved in 15 mL of acetic acid and then methyl 2- (bromomethyl) -5-nitro-benzoic acid 25a (1.1 g, 4.0 mmol) was added. . The reaction mixture was heated to 110 ^° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature. A large amount of solid precipitated and was filtered. The filter cake was dried to give the title compound 6-nitro-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one 49b (300 mg, 23.2%) as a white solid.
MS m / z (ESI): 323.0 [M + 1]

Process 2
6-Amino-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one
Dissolve 6-nitro-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one 49b (300 mg, 0.93 mmol) in 40 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) After that, Raney nickel (30 mg) was added. The reaction mixture was stirred for 16 hours under hydrogen atmosphere. The reaction mixture was filtered through ceratom and the filter cake was washed with 30 mL ethyl acetate. The filtrates were combined and concentrated under reduced pressure to give a crude product (272 mg) of the title compound 6-amino-2- (3- (trifluoromethyl) -phenyl) isoindoline-1-one 49c as a black solid. This was used in the next step without further purification.
MS m / z (ESI): 293.2 [M + 1]

Process 3
2- (3- (Trifluoromethyl) phenyl) isoindoline-5-amine Lithium aluminum hydride (70 mg, 1.86 mmol) was added to 10 mL of tetrahydrofuran and then cooled in an ice bath. To this solution was slowly added dropwise a tetrahydrofuran solution of 10 mL of 6-amino-2- (3- (trifluoromethyl) phenyl) isoindoline-1-one 49c (271 mg, 0,93 mmol). The ice bath was removed and the reaction mixture was heated to 65 ^° C. and stirred for 1 hour. To the reaction mixture was added 2 mL of 1 M sodium hydroxide solution and filtered. The filter cake was washed with 20 mL ethyl acetate. The filtrates were combined and concentrated under reduced pressure to give a crude product (258 mg) of the title compound 2- (3- (trifluoromethyl) phenyl) isoindoline-5-amine 49d as a black solid. This was used in the next step without further purification.
MS m / z (ESI): 279.1 [M + 1]

Process 4
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotine Amide
2- (3- (trifluoromethyl) phenyl) isoindoline-5-amine 49d (258 mg, 0.93 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino ) Methyl) nicotinic acid 14b (270 mg, 0.93 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (357 mg, 01.86 mmol), 1-hydroxybenzotriazole (13 mg, 0.093 mmol) and Triethylamine (375 mg, 3.72 mmol) was added sequentially to 5 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to afford the title compound 2- (difluoromethyl) -5-(((2-fluoro -2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotinamide 49 (25 mg, 4.9% over 3 steps) was obtained. .
MS m / z (ESI): 551.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.79 (s, 1H), 8.87 (br, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.41 (d, 1H), 7.16 (s, 1H), 6.97 (t, 2H), 6.89 (s, 1H), 4.68 (d, 3H), 4.47 ( d, 2H), 4.39-4.44 (m, 1H), 1.54 (s, 3H), 1.48 (s, 3H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl-2H-indazol-5-yl) Nicotinamide

Process 1
5-Nitro-2- (3- (trifluoromethyl) phenyl) -2H-indazole
2- (3- (trifluoromethyl) phenyl) indazole 50a (28 mg, 0.11 mmol) and sodium nitrate (14.5 mg, 0.17 mmol) were added to 1 mL of concentrated sulfuric acid. The reaction mixture was heated to 70 ^° C. and stirred for 0.5 hour. The reaction mixture was cooled to room temperature, poured into 20 mL saturated sodium carbonate solution, and then extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 5-nitro-2- (3- (trifluoromethyl) -phenyl) -2H-indazole 50b (30 mg, 91.5%) as a yellow solid.
MS m / z (ESI): 308.1 [M + 1]

Process 2
2- (3- (Trifluoromethyl) phenyl) -2H-indazolyl-5-amine
After dissolving 5-nitro-2- (3- (trifluoromethyl) phenyl) -2H-indazole 50b (30 mg, 0.098 mmol) in 10 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1) Raney nickel (10 mg) was added. The reaction mixture was stirred for 1 hour under a hydrogen atmosphere and filtered through Ceratom. The filtrate was concentrated under reduced pressure to give a crude product (25 mg, 92.6%) of the title compound 2- (3- (trifluoromethyl) phenyl) -2H-indazolyl-5-amine 50c as a yellow solid.
MS m / z (ESI): 278.1 [M + 1]

Process 3
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl-2H-indazol-5-yl) Nicotinamide
2- (3- (trifluoromethyl) phenyl) -2H-indazolyl-5-amine 50c (25 mg, 0.090 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl ) Amino) methyl) nicotinic acid 14b (26 mg, 0.090 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (35 mg, 0.18 mmol), 1-hydroxybenzotriazole (1.2 mg, 9.02 μmol) And triethylamine (50 μL, 0.36 mmol) was added sequentially to 5 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to afford the title compound 2- (difluoromethyl) -5-(((2-fluoro -2-Methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) -2H-indazol-5-yl) nicotinamide 50 (14 mg, 28.6%) was obtained.
MS m / z (ESI): 550.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.80 (s, 1H), 9.30 (s, 1H), 8.89 (br, 1H), 8.70 (s, 1H), 8.44 (d, 2H), 8.37 (s, 1H), 7.85 (s, 1H), 7.76-7.81 (m, 2H), 7.77 (d, 1H), 7.48 (d, 1H), 7.20 (t, 1H), 4.47 (d, 2H), 1.54 (s, 3H), 1.48 (s, 3H).

N- (2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide

Process 1
2- (4-Chlorophenyl) -1-ethyl-5-nitro-benzo [d] imidazole
2- (4-Chlorophenyl) -5-nitro-1H-benzo [d] imidazole 51e (600 mg, 2.29 mmol, prepared according to the method disclosed in Monatshefte fuer Chemie, 2009, 140 (5), 547-552 Were dissolved in 40 mL of N, N-dimethylformamide, and sodium hydride (87 mg, 2.29 mmol) was added. The reaction mixture was stirred for 0.5 hour, iodoethane (512 mg, 3.28 mmol) was added, and the mixture was further stirred for 3 hours. After the reaction is complete, the reaction mixture is quenched with 30 mL of water, extracted with ethyl acetate (30 mL × 3), washed with a saturated solution of sodium chloride (30 mL × 2), and anhydrous sulfuric acid. Dry over sodium and filter. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system A to give the yellow-doped title compound 2- (4-chlorophenyl) -1-ethyl-5-nitro-benzo [ d] Imidazole 51f (540 mg, 82.0%) was obtained.
MS m / z (ESI): 302.1 [M + 1]

Process 2
2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-amine
2- (4-Chlorophenyl) -1-ethyl-5-nitro-1H-benzo [d] imidazole 51f (150 mg, 0.49 mmol) was dissolved in 10 mL of methanol, and Raney nickel (15 mg) was added. The reaction mixture was stirred at room temperature for 14 hours under hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (100 mg) of 51 g of the brown-doped title compound 2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-amine. This was used in the next step without further purification.
MS m / z (ESI): 272.2 [M + 1]

Process 3
N- (2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) nicotinamide
2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-amine 51g (50 mg, 0.87 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) Methyl) nicotinic acid 1f (80 mg, 0.87 mmol), 1-hydroxybenzotriazole (25 mg, 0.87 μmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (70 mg, 0.367 mmol) Were sequentially added to 3 mL of N, N-dimethylacetamide. The reaction mixture was stirred at 40 ^° C. for 3.5 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound N- (2- (4-chlorophenyl) -1 -Ethyl-1H-benzo [d] imidazol-5-yl) -2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) -nicotinamide 51 (40 mg, 40%) was obtained. .
MS m / z (ESI): 526.7 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.50 (br, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.55 (s, 1H), 8.13 (d, 2H), 8.10 (s, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.56 (s, 2H), 6.47 (s, 1H), 4.51 (s, 2H), 4.15 (m, 2H), 2.71 ( m, 1H), 1.30 (m, 3H), 1.15 (m, 6H).

2-Chloro-N- (2- (4-chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
2- (4-Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-amine 51g (50 mg, 0.87 mmol), 2-chloro-5-((2,2-dimethylpropanoylamino) methyl ) Benzoic acid 2a (100 mg, 0.87 mmol), 1-hydroxybenzotriazole (25 mg, 0.87 μmol) and 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (70 mg, 0.367 mmol) Sequentially added to 3 mL of N, N-dimethylformamide. The reaction mixture was stirred at 40 ^° C. for 3.5 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a soil-like yellow solid, ie the title compound 2-chloro-N- (2- (4 -Chlorophenyl) -1-ethyl-1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 52 (10 mg, 10.7%) was obtained.
MS m / z (ESI): 523.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.39 (br, 1H), 8.18 (d, 2H), 8.10 (s, 1H), 7.70 (s, 1H), 7.66 (d, 1H), 7.58 (m, 2H), 7.56-7.53 (m, 3H), 4.26 (s, 2H), 4.16 (m, 2H), 1.30 (m, 4H), 1.21 (s, 9H).

2-Chloro-N- (2- (5-chloropyridin-2-yl) -1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide

Process 1
2- (5-Chloropyridin-2-yl) -5-nitro-1H-benzo [d] imidazole
4-Nitrobenzene-1,2-diamine 53a (400 mg, 2.6 mmol), 5-chloropyridine-2-carbaldehyde 53b (92 mg, 0.65 mmol) and 10 mL of 6N hydrochloric acid were mixed well. The resulting mixture was stirred at 65 ^° C. for 12 hours. The reaction mixture was filtered and the filter cake was washed with water (20 mL) and dried to give the title compound 2- (5-chloropyridin-2-yl) -5-nitro-1H-benzo [d] imidazole as a yellow solid 53c crude product (350 mg) was obtained. This was used in the next step without further purification.
MS m / z (ESI): 275.1 [M + 1]

Process 2
2- (5-Chloropyridin-2-yl) -1H-benzo [d] imidazol-5-amine
2- (5-chloropyridin-2-yl) -5-nitro-1H-benzo [d] imidazole 53c (120 mg, 0.44 mmol) was dissolved in 20 mL of tetrahydrofuran and 20 mL of methanol, and then Raney nickel (100 mg) was added. The reaction mixture was stirred for 12 hours under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to give a dark yellow oil, ie crude product of the title compound 2- (5-chloropyridin-2-yl) -1H-benzo [d] imidazol-5-amine 53d (110 mg) Got. This was used in the next step without further purification.
MS m / z (ESI): 245.1 [M + 1]

Process 3
2-Chloro-N- (2- (5-chloropyridin-2-yl) -1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
2-Chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (58 mg, 0.20 mmol) was dissolved in 10 mL of tetrahydrofuran, and then N, N-diisopropylethylamine (53 mg, 0.41 mmol) and 2- (5-chloropyridin-2-yl) -1H-benzo [d] imidazol-5-amine 53d (50 mg, 0.20 mmol) were added. The resulting mixture was stirred for 12 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2-chloro-N- (2- (5-chloropyridine). -2-yl) -1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 53 (20 mg, 20%) was obtained.
MS m / z (ESI): 496.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.82 (s, 1H), 8.71 (s, 1H), 8.35 (d, 1H), 8.18 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.57-7.52 (m, 5H), 5.5 (s, 1H), 4.30 (d, 2H), 1.13 (s, 9H).

2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-yl) nicotinamide

Process 1
6-nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole Sodium nitrate (27 mg, 0.32 mmol) and 1 mL of concentrated sulfuric acid were mixed, and the temperature was kept below 75 ^° C. 2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole 54a (50 mg, 0.18 mmol, prepared according to the method disclosed in Journal of Molecular Structure, 2012, 1011, 81-93) Slowly added. After the addition was complete, the reaction mixture was stirred at 70 ^° C. for 1 hour. After adjusting the pH of the reaction mixture to 9 with sodium hydroxide solution (50%), 50 mL of ethyl acetate and 20 mL of water were added. The organic layer was concentrated under reduced pressure to obtain a crude product (58 mg) of the title compound 6-nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole 54b as a yellow solid. This was used in the next step without further purification.
MS m / z (ESI): 325.1 [M + 1]

Process 2
2- (4- (Trifluoromethyl) phenyl) benzo [d] thiazol-6-amine
6-Nitro-2- (4- (trifluoromethyl) phenyl) benzo [d] thiazole 54b (58 mg, 0.179 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of methanol, and Raney nickel (5 mg) was added. added. The reaction mixture was stirred for 20 minutes under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to give a pale yellow solid, ie, crude product (53 mg) of the title compound 2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-amine 54c. This was used in the next step without further purification.
MS m / z (ESI): 295.1 [M + 1]

Process 3
2- (Difluoromethyl) -5-((2-methylpropanoylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-yl) nicotinamide
2- (4- (Trifluoromethyl) phenyl) benzo [d] thiazol-6-amine 54c (53 mg, 0.18 mmol), 2- (difluoromethyl) -5-((2-methylpropanoylamino) methyl) 5 mL nicotinic acid 1f (49 mg, 0.18 mmol), 1-hydroxybenzotriazole (25 mg, 0.18 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (52 mg, 0.27 mmol) Of N, N-dimethylacetamide. The reaction mixture was stirred at 40 ^° C. for 1 hour. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give the title compound 2- (difluoromethyl) -5-((2-methylprop Noylamino) methyl) -N- (2- (4- (trifluoromethyl) phenyl) benzo [d] thiazol-6-yl) nicotinamide 54 (20 mg, 20%) was obtained.
MS m / z (ESI): 529.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 8.67 (s, 1H), 8.45 (d, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.89 -7.87 (m, 4H), 7.54 (d, 1H), 7.46 (d, 1H), 7.43 (t, 1H), 4.42 (d, 2H), 3.17-3.16 (m, 1H), 1.05 (s, 6H ).

2-Chloro-N- (2- (4-chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide

Process 1
2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-benzo [d] imidazole
2- (4-Chlorophenyl) -5-nitro-1H-benzo [d] imidazole 51e (600 mg, 2.2 mmol), iodomethane (0.47 mg, 3.3 mmol) and cesium carbonate (2.15 g, 6.6 mmol) were mixed. The reaction mixture was stirred for 12 hours. After the reaction was complete, the reaction mixture was poured into 50 mL of water and filtered. The filter cake was washed with water (20 mL) and dried to give a crude product of the title compound 2- (4-chlorophenyl) -1-methyl-5-nitro-1H-benzo [d] imidazole 55a as a yellow solid (0.35 g ) This was used in the next step without further purification.
MS m / z (ESI): 288.2 [M + 1]

Process 2
2- (4-Chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-amine
2- (4-Chlorophenyl) -1-methyl-5-nitro-1H-benzo [d] imidazole 55a (320 mg, 1.11 mmol) was dissolved in 1 mL of tetrahydrofuran and 1 mL of methanol, and then Raney nickel (50 mg ) Was added. The reaction mixture was stirred for 12 hours under hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure to give a yellow oil, ie crude product (112 mg) of the title compound 2- (4-chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-amine 55b. . This was used in the next step without further purification.
MS m / z (ESI): 258.1 [M + 1]

Process 3
2-Chloro-N- (2- (4-chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
2- (4-Chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-amine 55b (50 mg, 0.19 mmol) was dissolved in 10 mL of tetrahydrofuran, and then 2-chloro-5-((2 , 2-Dimethylpropanoylamino) methyl) benzoyl chloride 2b (56 mg, 0.19 mmol) and N, N-diisopropylethylamine (52 mg, 0.39 mmol) were added. The resulting mixture was stirred at 65 ^° C. for 2 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure and the residue is purified sequentially by thin layer chromatography (TLC) using elution system A and HPLC to give a pale yellow solid, ie the title compound 2-chloro- N- (2- (4-Chlorophenyl) -1-methyl-1H-benzo [d] imidazol-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 55 (10 mg, 10.1 %).
MS m / z (ESI): 509.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.37 (br, 1H), 8.16 (d, 2H), 8.12 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.68 (d, 1H), 7.59 (m, 2H), 7.58-7.55 (m, 3H), 4.28 (d, 2H), 3.98 (s, 3H), 1.23 (s, 9H).

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole-5- Il) Nicotinamide

Process 1
5-Nitro-2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole A flask was charged with 10 mL of polyphosphoric acid and heated to 120 ^° C. 3- (Trifluoromethyl) benzoic acid 56a (1.48 g, 7.79 mmol) and 2-amino-4-nitro-phenol 56b (1.0 g, 6.49 mmol) were added in several portions. The resulting mixture was stirred at 120 ^° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into 50 mL of 1N sodium hydroxide solution. The pH of this solution was adjusted to 8-9 with 1N sodium hydroxide solution in an ice bath, extracted with ethyl acetate (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography (TLC) using elution system B to give the title compound 5-nitro-2- (3- (trifluoromethyl) phenyl) benzo [ d] Oxazole 56c (0.26 g, 10%) was obtained.
MS m / z (ESI): 308.9 [M + 1]

Process 2
2- (3- (Trifluoromethyl) phenyl) benzo [d] oxazol-5-amine
5-Nitro-2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole 56c (100 mg, 0.3 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of methanol, and Raney nickel (30 mg) was added. added. The reaction mixture was stirred for 1 hour under hydrogen atmosphere. The reaction mixture was then filtered through ceratom. The filtrate was concentrated under reduced pressure to give a yellow oil, ie, crude product (100 mg) of the title compound 2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 56d. This was used in the next step without further purification.
MS m / z (ESI): 279.1 [M + 1]

Process 3
2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzo [d] oxazole-5- Il) Nicotinamide
2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-amine 56d (100 mg, 0.325 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl- Propanoyl) amino) methyl) nicotinic acid 14b (94 mg, 0.325 mmol), 1-hydroxybenzotriazole (4.0 mg, 0.03 μmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (125 mg, 0.65 mmol) and triethylamine (0.18 mL, 1.3 mmol) were added to 10 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 2 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2- (difluoromethyl) -5-(((( 2-Fluoro-2-methyl-propanoyl) amino) methyl) -N- (2- (3- (trifluoromethyl) phenyl) benzo [d] oxazol-5-yl) nicotinamide 56 (190 mg, 56%) Got.
MS m / z (ESI): 551.3 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.94 (s, 1H), 8.88 (br, 1H), 8.71 (d, 1H), 8.51 (d, 1H), 8.46 (s, 1H), 8.27 (d, 1H), 8.05 (d, 2H), 7.89-7.97 (m, 1H), 7.84-7.88 (m, 1H), 7.72 (dd, 1H), 7.20 (t, 1H), 4.48 (d, 2H ), 1.54 (s, 3H), 1.49 (s, 3H).

2-Chloro-N- (2- (4-chlorophenyl) -3-oxo-isoindoline-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide

Process 1
2- (4-Chlorophenyl) -6-nitro-isoindoline-1-one methyl 2- (bromomethyl) -5-nitro-benzoic acid 25a (200 mg, 0.73 mmol), 4-chloroaniline (112 mg, 0.88 mmol ) And N, N-diisopropylethylamine (113 mg, 0.88 mmol) were added to 5 mL of ethanol. The reaction mixture was heated to 110 ^° C. and stirred for 16 hours. The reaction mixture was then cooled to room temperature and filtered. The filter cake was washed with ethanol (0.5 mL × 2) and dried to give the title compound 2- (4-chlorophenyl) -6-nitro-isoindoline-1-one 57a (160 mg, 76.2%) as a yellow solid. It was.
MS m / z (ESI): 289.0 [M + 1]

Process 2
6-Amino-2- (4-chlorophenyl) isoindoline-1-one
2- (4-Chlorophenyl) -6-nitro-isoindoline-1-one 57a (160 mg, 0.55 mmol) was dissolved in 20 mL of a mixture of tetrahydrofuran and methanol (V: V = 1: 1). (50 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was then filtered through Ceratom and the filtrate was concentrated under reduced pressure to give a crude product (160 mg) of the title compound 6-amino-2- (4-chlorophenyl) isoindoline-1-one 57b as a white solid. It was. This was used in the next step without further purification.
MS m / z (ESI): 259.1 [M + 1]

Process 3
2-Chloro-N- (2- (4-chlorophenyl) -3-oxo-isoindoline-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide
6-Amino-2- (4-chlorophenyl) isoindoline-1-one 57b (80 mg, 0.31 mmol) and triethylamine (0.2 mL, 1.49 mmol) were dissolved in 10 mL of acetonitrile and then in an ice bath. 2 mL of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (74 mg, 0,26 mmol) in dichloromethane was added. The reaction mixture was stirred for 1 hour. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2-chloro-N- (2- (4- (4- Chlorophenyl) -3-oxo-isoindoline-5-yl) -5-((2,2-dimethylpropanoylamino) methyl) benzamide 57 (15 mg, 15.9% over 2 steps) was obtained.
MS m / z (ESI): 511.2 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.82 (s, 1H), 8.27 (s, 1H), 8.19 (t, 1H), 7.97 (d, 2H), 7.65 (d, 1H), 7.54 (d, 1H), 7.50-7.53 (m, 3H), 7.46 (s, 1H), 7.37 (d, 1H), 5.01 (s, 2H), 4.30 (s, 2H), 1.13 (s, 9H).

2-Chloro-N- (3-oxo-2- (4- (trifluoromethyl) phenyl) isoindoline-5-yl) -5-((2,2-dimethyl-propanoyl) amino) methyl) -benzamide
6-Amino-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25c (82 mg, 0.28 mmol) and triethylamine (0.2 mL, 1.49 mmol) were dissolved in 10 mL of dichloromethane, and then iced. In the bath, 10 mL of 2-chloro-5-((2,2-dimethylpropanoylamino) methyl) benzoyl chloride 2b (80 mg, 0,28 mmol) in dichloromethane was added. The reaction mixture was stirred for 1 hour. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2-chloro-N- (3-oxo-2 -(4- (Trifluoromethyl) phenyl) isoindoline-5-yl) -5-((2,2-dimethyl-propanoyl) amino) methyl) -benzamide 58 (4 mg, 2.6%) was obtained.
MS m / z (ESI): 544.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.84 (s, 1H), 8.30 (d, 1H), 8.17 (d, 3H), 7.87 (d, 1H), 7.82 (s, 2H), 7.70 (d, 1H), 7.55 (d, 1H), 7.47 (s, 1H), 7.38 (d, 1H), 5.08 (s, 2H), 4.30 (d, 2H), 1.13 (s, 9H)

2- (Difluoromethyl) -5-(((2-fluoro-2-methyl-propanoyl) amino) methyl) -N- (3-oxo-2- (3- (trifluoromethyl) phenyl) isoindoline-5 -Ill) Nicotinamide
6-amino-2- (4- (trifluoromethyl) phenyl) isoindoline-1-one 25c (100 mg, 0.34 mmol), 2- (difluoromethyl) -5-(((2-fluoro-2-methyl -Propanoyl) amino) methyl) nicotinic acid 14b (100 mg, 0.34 mmol), 1-ethyl- (3-dimethylaminopropyl) -carbodiimide hydrochloride (130 mg, 0.69 mmol), 1-hydroxybenzotriazole (5.0 mg, 37 μmol) and triethylamine (140 μL, 1.03 mmol) were added to 5 mL of N, N-dimethylacetamide. The reaction mixture was stirred for 16 hours. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin layer chromatography (TLC) using elution system A to give a pale yellow solid, ie the title compound 2- (difluoromethyl) -5-(((( 2-Fluoro-2-methyl-propanoyl) amino) methyl) -N- (3-oxo-2- (3- (trifluoromethyl) phenyl) isoindoline-5-yl) nicotinamide 59 (80 mg, 41.5% )
MS m / z (ESI): 565.1 [M + 1]
¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.02 (s, 1H), 8.89 (br, 1H), 8.71 (d, 1H), 8.45 (s, 1H), 8.27 (d, 1H), 8.13 (d, 1H), 8.06 (s, 1H), 7.91 (d, 1H), 7.70 (d, 2H), 7.55 (d, 1H), 7.20 (t, 1H), 5.11 (s, 2H), 4.48 ( d, 2H), 1.54 (s, 3H), 1.48 (s, 3H).

Test example

Biological efficacy test

Test example 1

Inhibitory activity of the compound of the present invention against human mPGES1 The method described here is used to measure the inhibitory activity of the compound of the present invention against human mPGES1.
I. Materials and equipment PGE2 assay kit (Cisbio, # 62P2APEB)
2. Prostaglandin H2 (sigma, # P7867-1MG)
3. FlexStation3 Microplate Reader
II. Test method Obtaining membrane protein of mPGES1 enzyme
The cell density of HEK-293 F was adjusted to 6 × 10 ⁵ / mL, and the gene was introduced the next day using a plasmid containing the human mPGES1 gene with the gene introduction reagent PEI. The cells were continuously cultured for 72 hours at 37 ° C. with shaking. Cells were harvested after centrifugation at 1100 g for 5 minutes. After sonication in an ice bath and centrifugation at 5000 g for 10 minutes, a supernatant was obtained. The supernatant was centrifuged at 100,000 g for 1 hour to obtain a precipitate. The precipitate was resuspended in storage buffer containing 10% glycerin, subpackaged, snap frozen under liquid nitrogen and stored at -80 ° C.
2. mPGES1 enzyme assay
mPGES1 is diluted in test buffer and added to the plate as 49 μL / well and 1 μL of compound (7 gradient concentrations: 10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM and 0.01 nM) The final concentration of each compound was added. To each well, 3.8 μL of 20 μg / mL PGH that had been shaken for 30 seconds and then pre-cooled with ice was added and incubated on ice for 7 minutes. The reaction was then quenched by adding 53.8 μL of 6 mg / mL SnCl ₂ to each well. Samples were diluted 1: 400 with dilution buffer. 10 μL of diluted sample, 5 μL PGE2-d2 and 5 μL anti-PGE2 cryptate were added to black 384-well plates and incubated at 4 ° C. overnight. HTRF was measured using a flexstation and the IC ₅₀ of the compound was obtained by data processing software.
The inhibitory activity of the compounds of the present invention for mPGES1 was tested by the above test method. IC ₅₀ values are shown in Table 1 below.
Conclusion: The compound of the present invention has a remarkable inhibitory activity against human mPGES1 protein.

Test example 2

Inhibitory activity of the compound of the present invention against guinea pig mPGES1 The method described here is used to measure the inhibitory activity of the compound of the present invention against guinea pig mPGES1.
I. Materials and equipment PGE2 assay kit (Cisbio, # 62P2APEB)
2. Prostaglandin H2 (sigma, # P7867-1MG)
3. FlexStation3 Microplate Reader
II. Test method Obtaining membrane protein of mPGES1 enzyme
The cell density of HEK-293 F was adjusted to 6 × 10 ⁵ / mL, and the gene was introduced the next day using a plasmid containing the human mPGES1 gene with the gene introduction reagent PEI. The cells were continuously cultured for 72 hours at 37 ° C. with shaking. Cells were collected after centrifugation at 1100 g for 5 minutes. After sonication in an ice bath and centrifugation at 5000 g for 10 minutes, a supernatant was obtained. The supernatant was centrifuged at 100,000 g for 1 hour to obtain a precipitate. The precipitate was resuspended in storage buffer containing 10% glycerin, subpackaged, snap frozen under liquid nitrogen and stored at -80 ° C.
2. mPGES1 enzyme assay
mPGES1 is diluted in test buffer and added to the plate as 49 μL / well to add 1 μL of compound (7 gradient concentrations: 10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM and 0.01 nM) (Final concentration of each compound at). To each well, 3.8 μL of 20 μg / mL PGH that had been shaken for 30 seconds and then pre-cooled with ice was added and incubated on ice for 7 minutes. The reaction was then quenched by adding 53.8 μL of 6 mg / mL SnCl ₂ to each well. Samples were diluted 1: 400 with dilution buffer.
10 μl of diluted sample, 5 μL PGE2-d2 and 5 μL anti-PGE2 cryptate were added to black 384-well plates and incubated at 4 ° C. overnight. HTRF was measured using a flexstation and the IC ₅₀ of the compound was obtained by data processing software. The inhibitory activity of the compounds of the present invention for mPGES1 was tested by the above test method. IC ₅₀ values are shown in Table 2 below.
Conclusion: The compounds of the present invention have significant activity against guinea pig mPGES1 protein.

Test example 3

Inhibitory activity of the compounds of the present invention on the secretion of PGE2 by A549 cells under the stimulation of IL-1β The method described here demonstrates the inhibitory activity of the compounds of the present invention on the secretion of PGE2 by A549 cells under the stimulation of IL-1β. Used to measure.
I. Materials and equipment PGE2 assay kit (Cisbio, # 62P2APEB)
2. IL-1β (Peprotech, # AF-200-01B)
3. Cell line: A549 (ATCC: CCL-185)
4). FlexStation3 Microplate Reader
II. Test Method On the first day, A549 cells were seeded in 96-well plates at 40000 / well. On day 2, the 96-well plate broth was removed and diluted with broth (11111 nM, 11111 nM, 111 nM, 11.11 nM, 1.11 nM, 0.11 nM and 0.011 nM at seven gradient concentrations). 90 μL of each compound concentration) was added. Cells were incubated for 30 minutes at 37 ° C. in a thermostat and IL-1β was added to a final concentration of 0.2 ng / mL. The cells were then incubated for an additional 24 hours at 37 ° C. On day 3, 10 μl supernatant, 5 μL PGE2-d2 and 5 μL anti-PGE2 cryptate were added to black 384-well plates and incubated at 4 ° C. overnight. HTRF was measured using a flexstation and the IC ₅₀ of the compound was obtained by data processing software.
The inhibitory activity of the compounds of the present invention on the secretion of PGE2 by A549 cells under the stimulation of IL-1β was tested by the test method described above. IC ₅₀ values are shown in Table 3 below.

Conclusion: The compounds of the present invention have a significant inhibitory activity on the secretion of PGE2 by A549 cells under the stimulation of IL-1β.
Pharmacokinetic study

Test example 4

Pharmacokinetic study of the compounds of the present invention Summary Rats were used as test animals. The drug concentrations in plasma at different time points were determined as in Example 8, Example 11, Example 14, Example 17, Example 20, Example 27, Example 33, Example 35, Example 36, Example 37 and The compound of Example 48 was measured by LC / MS / MS after administration to rats. The pharmacokinetic behavior of the compounds of the present invention was studied and evaluated in rats.
2. Protocol 2.1 Sample Compounds of Example 8, Example 11, Example 14, Example 17, Example 20, Example 27, Example 33, Example 35, Example 36, Example 37 and Example 48 2.2 Test animals
44 healthy adult Sprague-Dawley (SD) rats, female and male, both purchased from SINO-BRITSH SIPPR / BK LAB. ANIMAL LTD., CO. (With certificate, No .: SCXK (Shanghai) 2008 -0016), each group was divided into 11 groups of 4 animals.
2.3 Preparation of Test Compound An appropriate amount of the test compound was weighed, mixed with 25 μL Tween 80 and Labrasol, and a 0.6 mg / mL suspension was prepared by sonication.
2.4 Administration After overnight fasting, 44 SD rats, female and half male, were divided into 11 groups and administered intragastrically at a dose of 5.0 mg / kg and a dose volume of 10 mL / kg.
3. Methods Blood (0.1 mL) was sampled from the orbital venous plexus before administration and at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours after administration. Samples were stored in EDTA anticoagulants and plasma was separated by centrifugation at 3,500 rpm for 5 minutes. Plasma samples were stored at -20 ° C. Rats were fed 2 hours after dosing.
Plasma concentrations of test compounds in rats after intragastric administration were measured by LC-MS / MS. The linearity of the method is 5.00-2000 ng / mL and 1.00-2000 ng / mL, and the minimum for quantification is 5.00 ng / mL and 1.00 ng / mL. Plasma samples were analyzed after pretreatment by protein precipitation.
4). Results of pharmacokinetic parameters The pharmacokinetic parameters of the compounds of the present invention are shown below.
Conclusion: The compound of the present invention has good pharmacokinetic data and excellent pharmacokinetic absorption effect.

Claims (18)

Compounds of general formula (I), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
In the formula:
Ring P is selected from 5-membered heteroaryl and 5-membered heterocyclyl;
Ring Q is selected from aryl and heteroaryl;
A, B or Y is selected from -CH- and N;
R ¹ is selected from alkyl and cycloalkyl, which alkyl or cycloalkyl may be optionally further substituted with one or more groups selected from the group consisting of alkyl, halogen and haloalkyl;
R ² is selected from halogen and haloalkyl;
R ³ is the same or different and each independently represents hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, oxo, —C (O) OR ⁵ , —OC (O) R ⁵ , —NHS ( O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) Selected from NR ⁶ R ⁷ , wherein the alkyl, cycloalkyl and heterocyclyl are each halogen, hydroxyl, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC Optionally further substituted with one or more groups selected from the group consisting of (O) NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ ;
R ⁴ is selected from aryl and heteroaryl, wherein the aryl and heteroaryl are each halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ ,- Optionally further substituted with one or more groups selected from the group consisting of OC (O) NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ , wherein the haloalkyl is preferably trifluoromethyl ;
R ⁵ is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, aryl and heteroaryl are each alkyl, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Optionally further substituted with one or more groups selected from the group consisting of aryl, heteroaryl, carboxylic acid and carboxylate groups;
R ⁶ and R ⁷ are each independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently alkyl Optionally further substituted with one or more groups selected from the group consisting of, halogen, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate groups;
Or
R ⁶ and R ⁷ together with the nitrogen atom to which they are attached may form a heterocyclyl, wherein the heterocyclyl is one or more selected from the group consisting of N, O and S (O) _m It may contain heteroatoms, and the heterocyclyl is one or more selected from the group consisting of alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid and carboxylate groups Optionally further substituted with groups;
m is 0, 1 or 2;
s is an integer between 0 and 3;
t is 0 or 1. Compounds of formula (II), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;
(Where:
X is selected from -CH- and N;
Rings P, A, B, Y, s, t and R ^{1 to} R ⁴ are as defined in claim 1. Or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Salt. A compound of formula (III), formula (IV), or formula (V), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Made salt:
(Where:
X is selected from -CH- and N;
E, G and W are each independently selected from CR ^a , NR ^b , N, O and S;
R ^a and R ^b are each independently hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ is selected from the alkyl, cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} - OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) Optionally further substituted with one or more groups selected from the group consisting of NR ⁶ R ⁷ and —C (O) NR ⁶ R ⁷ ; and
A, B, Y, t, R ^{1 to} R ² and R ^{4 to} R ⁷ are as defined in claim 1. )
The compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Compounds of formula (VI), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
(Where:
X is selected from -CN and N;
R ^b is hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} -OC (O) R 5, - NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C ( O) optionally further substituted with one or more groups selected from the group consisting of NR ⁶ R ⁷ ; and
A, B, Y, t, R ^{1 to} R ² and R ^{4 to} R ⁷ are as defined in claim 1. )
The compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Compounds of formula (VII), or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
(Where:
X is selected from -CN and N;
R ^b is hydrogen, halogen, alkoxy, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, -C (O) OR ⁵ , -OC (O) R ⁵ , -NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) NR ⁶ R ⁷ cycloalkyl and heterocyclyl are each halogen, hydroxy, alkoxy, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, ^{heteroaryl, -C (O) oR 5,} -OC (O) R 5, - NHS (O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C ( O) optionally further substituted with one or more groups selected from the group consisting of NR ⁶ R ⁷ ;
R ⁸ is halogen, alkoxy, hydroxyl, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C (O) OR ⁵ , —OC (O) R ⁵ , —NHS ( O) mR ⁵ , -C (O) R ⁵ , -NHC (O) R ⁵ , -NHC (O) OR ⁵ , -NR ⁶ R ⁷ , -OC (O) NR ⁶ R ⁷ and -C (O) Selected from NR ⁶ R ⁷ , wherein the haloalkyl is preferably trifluoromethyl; and
A, B, Y, R ^{1 to} R ² and R ^{5 to} R ⁷ are as defined in claim 1. )
The compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.   6. A compound of formula (I) according to any one of claims 1 to 5, wherein A, B and Y are -CH-, or a tautomer, mesomer, racemate, enantiomer, diastereomer thereof. Mer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.   6. A compound of formula (I) according to any one of claims 1-5, wherein one of A, B and Y is N and the other two are -CH-, or a tautomer, mesomer thereof , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof. The group
But,
(R ³ and R ⁴ are as defined in claim 1)
3. The compound of formula (I) according to claim 1 or 2, selected from: tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceuticals thereof Acceptable salt. Wherein R ¹ is alkyl and haloalkyl, preferably tert-butyl, isopropyl,
Or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutical thereof, wherein the compound is selected from Acceptable salt. The compound is
A compound of formula (I) according to any one of claims 1 to 9, selected from: or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixtures thereof, Or a pharmaceutically acceptable salt thereof. A compound of formula (IA) or a salt thereof is reacted with a compound of formula (IB) to give a compound of formula (I):
Wherein R ^c is selected from hydroxy and halogen;
Ring P, ring Q, A, B, Y, s, t and R ^{1 to} R ⁴ are as defined in claim 1. )
A compound of formula (I) according to claim 1, or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof A method for producing a salt. The following groups:
(Where:
R ³ is selected from hydrogen, alkyl, and heterocyclyl, which alkyl is optionally further substituted with one or more groups selected from the group consisting of alkoxy and heterocyclyl;
R ⁴ is selected from aryl and heteroaryl, which aryl or heteroaryl may be optionally further substituted with one or more groups selected from the group consisting of halogen and haloalkyl, which haloalkyl is preferably trifluoro R ⁴ is preferably phenyl, which is further substituted with one halogen or haloalkyl;
t is 1;
However:
General formula (IA) is in the following groups:
When
R ³ is selected from hydrogen and alkyl, which alkyl is optionally further substituted with one or more groups selected from alkoxy and heterocyclyl;
R ⁴ is selected from phenyl, which is further substituted with one haloalkyl, which is preferably trifluoromethyl; or
R ³ is heterocyclyl;
R ⁴ is phenyl, which is further substituted with one halogen or haloalkyl. )
A compound of formula (IA) consisting of:
Or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. The compound is
13. A compound of formula (IA) according to claim 12, selected from: tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable thereof Salt. Compound is
Or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from:
(Where
R ^c is selected from hydroxy and halogen; and rings Q, R ¹ and R ² are as defined in claim 1).   Treatment of the compound of formula (I) according to claim 1 or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising an effective amount above and a pharmaceutically acceptable carrier, diluent or excipient.   11. A compound of formula (I) according to any one of claims 1 to 10, or a tautomer thereof, in the manufacture of a medicament for the treatment of a disease mediated by microsomal prostaglandin E synthase-1. , Mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, or use of a pharmaceutical composition according to claim 15.   11. A compound of formula (I) according to any one of claims 1 to 10, or a tautomer, mesomer, racemate thereof, in the manufacture of a medicament for inhibiting microsomal prostaglandin E synthase-1. 16. Use of a body, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15.   The disease or disorder is inflammation, pain, cancer, diabetes and diabetic complications or neurodegenerative disease, preferably inflammation or pain, more preferably osteoarthritis, rheumatoid arthritis, bursitis, ankylosing spondylitis, or these 11. The manufacture of a medicament for the treatment and / or prevention of a disease or disorder selected from the group consisting of pain associated with any one of the disease or disorder. 16. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or Use of a pharmaceutical composition.